ArticlePDF AvailableLiterature Review

Mitochondrial Dysfunction in Primary Ovarian Insufficiency

August 2019
Endocrinology 160(10)

August 2019
160(10)

DOI:10.1210/en.2019-00441

Authors:

Dov Tiosano

Ministry of Health (Israel)

Jason A Mears

Case Western Reserve University

Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1-2% of women, although the etiology of the majority of cases remains unexplained. Approximately 10-20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data is scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to the majority of POI cases that lack a known etiology. Further studies will be needed to better elucidate the contribution of mitochondria to POI and whether there is a common molecular defect in mitochondrial function that distinguishes mitochondrial-related genes that when mutated cause POI versus those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.

Molecular functions of mitochondria-related proteins implicated in POI. A cartoon depicts the various molecular functions in mitochondria of the proteins in which mutations have been identified that can cause POI.

…

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Content uploaded by Jason A Mears

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MINI-REVIEW

Mitochondrial Dysfunction in Primary

Ovarian Insufficiency

Dov Tiosano,

1,2

Jason A. Mears,

3,4

and David A. Buchner

5,6,7

Division of Pediatric Endocrinology, Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa

3109601, Israel;

Rappaport Family Faculty of Medicine, Technion—Israel Institute of Technology, Haifa

3200003, Israel;

Center for Mitochondrial Diseases, Case Western Reserve University, Cleveland, Ohio

44106;

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106;

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106;

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106; and

Research

Institute for Children’s Health, Case Western Reserve University, Cleveland, Ohio 44106

ORCiD numbers: 0000-0003-3920-4871 (D. A. Buchner).

Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles as-

sociated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep distur-

bances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular

disease. POI occurs in ;1% to 2% of women, although the etiology of most cases remains un-

explained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a

chromosomal abnormality, which has provided considerable molecular insight into the biological

underpinnings of POI. Many of the genes for which mutations have been associated with POI,

either isolated or syndromic cases, function within mitochondria, including MRPS22,POLG,

TWNK,LARS2,HARS2,AARS2,CLPP,andLRPPRC. Collectively, these genes play roles in mito-

chondrial DNA replication, gene expression, and protein synthesis and degradation. Although

mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are

scant as to whether these genes in particular, and mitochondrial dysfunction in general, con-

tribute to most POI cases that lack a known etiology. Further studies are needed to better

elucidate the contribution of mitochondria to POI and determine whether there is a common

molecular defect in mitochondrial function that distinguishes mitochondria-related genes that

when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial

dysfunction in POI suggests that manipulation of mitochondrial function represents an impor-

tant therapeutic target for the treatment or prevention of POI. (Endocrinology 160: 2353–2366,

2019)

Primary ovarian insufficiency (POI), which is also

commonly referred to as premature ovarian failure, is

defined by the loss or dysfunction of ovarian follicles

associated with amenorrhea before the age of 40 (1). POI

is a major cause of female infertility, with a prevalence

between 1% and 2%. It can occur spontaneously or be

the result of medical interventions such as removal of

the ovaries, chemotherapy, or radiation treatment.

Symptoms of POI are similar to menopause and com-

monly include hot flashes, sleep disturbances, vaginal

dryness, and night sweats (2). Other less commonly re-

ported symptoms include decreased energy, dry eyes, hair

loss, urinary incontinence, cold intolerance, cognitive

changes, depression, and joint pain, among others (3).

ISSN Online 1945-7170

Received 14 June 2019. Accepted 1 August 2019.

First Published Online 8 August 2019

Abbreviations: aaRS, aminoacyl-tRNA synthetase; AARS2, alanyl-tRNA synthetase 2,

mitochondrial; CLPP, caseinolytic mitochondrial matrix peptidase proteolytic subunit;

CLPX, caseinolytic mitochondrial matrix peptidase chaperone subunit; HARS2, histidyl-

tRNA synthetase 2, mitochondrial; LRPPRC, leucine-rich pentatricopeptide repeat containing;

MII, meiosis II; MRPS22, mitochondrial ribosomal pr otein S22; mtDNA, mitochondrial DNA;

OXPHOS, oxidative phosphorylation; POI, primary ov arian insufficiency; POLG, DNA polymerase

g, catalytic subunit; PRORP, protein-only RNase P catalytic subunit; ROS, reactive oxygen specie s;

TCA, tricarboxylic acid; TWNK, twinkle mtDNA helicase; WES, whole-exome sequencing.

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Longer-term consequences associated with the prema-

ture decrease in estrogen levels include increased risk of

cardiovascular disease and decreased bone mineral density

(4, 5). Symptom severity can be correlated with ovarian

function, as POI encompasses a range of decreased ovarian

functions from individuals with partial function who retain

fertility to those who completely lack ovarian function and

are infertile. Treatment will vary depending on the symp-

toms, but it can include hormone replacement therapy,

fertility management, and psychosocial support, as well as

annual screenings of thyroid and adrenal function (2).

In cases of POI that are not induced by chemotherapy

or radiation, the etiology is determined for only ;20% of

all cases (6). Approximately 5% of all POI cases are of

autoimmune origin, and 15% of cases have a clear ge-

netic origin, either in the form of a chromosomal ab-

normality or a mutation in an individual gene (7, 8).

Among the chromosomal abnormalities that are frequent

causes of POI are a number of X chromosome defects,

including Turner syndrome, triple X syndrome, and

fragile X syndrome. A number of monogenic disorders

resulting in POI have also been identified, with variants

in .50 genes having been associated with POI (8). The

genes that have been implicated in POI fall within a

number of pathways that are critical for ovarian devel-

opment and function, including DNA repair, meiosis,

germ cell recruitment, and steroidogenesis. Additionally,

mutations in many genes involved in mitochondrial

function have been identified as causes of POI. Thus, this

review summarizes the role of mitochondria in oocytes as

well as discusses the genetic causes of POI related to

mitochondrial dysfunction.

Mitochondrial Composition and Function

Mitochondria are maternally inherited double-

membrane organelles that are best known for their

role as the powerhouses of a cell, based on their gener-

ation of ATP via the process of oxidative phosphoryla-

tion (OXPHOS). The mitochondrial genome is ;16.7 kb

and encodes 13 proteins that function within the

OXPHOS pathway, as well as 22 tRNAs and 2 rRNAs.

However, estimates of the complete human mitochon-

drial proteome suggest the presence of at least 1500

proteins, and thus the vast majority of proteins localized

to mitochondria are encoded by the nuclear genome (9).

The proteomic complexity of mitochondria enables them

to perform many critical cellular functions beyond en-

ergy production such as macromolecule biogenesis (i.e.,

protein and nucleic acids), lipid synthesis, regulation of

cell death, calcium handling/homeostasis, generation

of reactive oxygen species (ROS), and antioxidant pro-

tection (10).

OXPHOS is the process by which nutrients are oxi-

dized by a series of five multisubunit protein complexes

(complex I to complex V) within the mitochondrial inner

membrane, ultimately resulting in the conversion of ADP

to ATP. During the process of ATP generation, mito-

chondria also release ROS in the form of superox-

ide. Although typically thought of as a byproduct

of OXPHOS that can damage cells, ROS possess anti-

microbial properties, act as signaling molecules, and

regulate autophagy (11). Nonetheless, excessive or

mislocalized ROS can have deleterious effects on the cell

and can induce oxidative damage to mitochondrial DNA

(mtDNA), the latter of which may be particularly sen-

sitive to damage due to the relative absence of DNA

repair enzymes in mitochondria (12). ROS are eliminated

in the mitochondria by three superoxide dismutases that

convert superoxide to hydrogen peroxide, which can

then be further converted to water by peroxiredoxins and

glutathione peroxidases.

Mitochondria are not static organelles, rather their

numbers are tightly regulated by balancing the processes

of mitochondrial biogenesis and clearance (13). Mito-

chondrial clearance can be mediated by the process of

mitophagy, which describes the degradation and recy-

cling of mitochondria via autophagy. Triggers for

mitophagy include mild increases in ROS (14) and the

inability to maintain an electrochemical gradient that can

result from the accumulation of mtDNA damage (15).

Mitochondrial biogenesis is then used to repopulate the

cellular mitochondrial population with more functional

mitochondria. The process of mitochondrial biogenesis

involves both fusion and fission events, and it is regulated

by a cascade of transcription and translation factors,

both nuclear and mitochondrial encoded, which serve to

generate the materials necessary for organelle duplication

(16). Mitochondrial fusion describes the merging of the

outer and then inner membranes of two previously

separate mitochondria, whereas mitochondrial fission is

the process by which a single mitochondrion divides into

two or more independent mitochondria. Mitochondrial

fusion, fission, and mitophagy collectively serve not only

an important quality control function, but can link

changes in mitochondrial abundance to cellular energy

demands (17). For example, nutrient deprivation pre-

vents mitochondrial fission, which together with other

molecular and structural changes to the mitochondria

serves to increase ATP synthesis capacity, whereas

thermogenesis or AMP-activated protein kinase activa-

tion serves to increase fission (18–20). Nutrient excess

inhibits fusion, resulting in an increase in fragmentation,

which can cause mitochondrial dysfunction and in-

crease ROS production (21). OXPHOS activity is posi-

tively correlated with fusion, although the causal nature

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of this relationship remains unclear (22). Mitophagy

can be triggered by energy stress via activation of

AMP-activated protein kinase, hypoxia, and glucose

deprivation (22). Collectively, the regulation of mito-

chondrial dynamics ensures that these organelles can help

the cell respond and adapt to a variety of cellular states to

match the bioenergetic and other mitochondrial func-

tions with the cellular energy needs.

Mitochondrial Function in Ovarian

Somatic Cells

Beyond the role of mitochondria in OXPHOS, ROS

homeostasis, apoptosis, and thermogenesis, mitochon-

dria have an important role in steroidogenesis. Ste-

roidogenesis occurs in the cumulus granulosa and theca

cells, which surround the oocyte, according to the two-

cell, two-gonadotropin model. The first step in ste-

roidogenesis, which is also the rate-limiting step, involves

the transport of cholesterol from the outer mitochondrial

membrane to the inner mitochondrial membrane by the

steroid acute regulatory protein (STAR) and other ac-

cessory proteins (23). Once inside the mitochondria,

cholesterol is metabolized to pregnenolone by cyto-

chrome P450 family 11 subfamily A member 1 (CYP11A1,

also known as P450SCC), which is then further me-

tabolized in the endoplasmic reticulum to form the final

steroid products, including estradiol and progesterone

(24, 25).

Mitochondrial Function in Oocytes

Oogenesis, the process by which a haploid oocyte is

formed within the ovary, originates from primordial

germ cells that arise in the extraembryonic mesoderm,

which then migrate to the genital ridge where they

proliferate by mitosis and transform to oogonia (26).

Following the arrest of mitosis, human germ cells initiate

meiosis in the fetal ovary at 11 to 12 weeks of gestation

and become primary oocytes (27). Oocytes enter meiosis

in the prophase stage, during which time homologous

chromosomes undergo synapsis and recombination.

Subsequent to the crossing over of genetic material

during recombination, oocytes progress to the diplotene

stage, which is defined by a protracted arrest. During

this resting state, oocytes become surrounded by pre-

granulosa cells to form primordial follicles, although

most oocytes undergo apoptosis during this process and

do not survive to form follicles (28). Oocyte survival

appears in part to depend on the transfer of organelles,

including Golgi and mitochondria, from nurse cells

connected by intercellular bridges that are associated

with the formation of a Balbiani body in the oocyte, a

structure that is densely packed with Golgi, endoplasmic

reticulum, and mitochondria (29, 30). The Balbiani body

is a transient formation and disappears in late-stage

oocytes. A subset of primordial follicles are further in-

duced via intra-oocyte and extra-oocyte factors involving

the phosphoinositide 3-kinase and mammalian target of

rapamycin pathways to transition to primary follicles

(31). The primary follicles then further develop to form

secondary follicles, which are surrounded by at least two

layers of granulosa cells and an outermost layer of theca

cells. The theca cells contain many mitochondria with

vesicular cristae (32). Further development preceding

ovulation includes the formation of a cavity called the

antrum and the selection of dominant follicles that will

eventually ovulate. Reinitiation of meiosis in the domi-

nant follicles can follow a surge of endogenous LH

during puberty, but these follicles can also remain in the

dormant state from the time of their formation during

fetal development until menopause, a period of ;50

years (33).

There is a tremendous increase in the number of mi-

tochondria per cell that occurs during oogenesis, from the

10 to 100 mitochondria found in primordial germ cells to

the .100,000 mitochondria found in a mature pre-

ovulatory oocyte (34). The small number of mitochon-

dria in primordial germ cells contributes to the

establishment of an inheritance bottleneck, in which

rapid shifts in the inheritance of mitochondrial variants

can occur between generations based on the small

number of mitochondria that form the basis of the rapid

expansion (35). Coupled with a dramatic reduction in

mtDNA in primordial germ cells, there exists a strong

selective pressure, including influence from the nuclear

genome, to eliminate deleterious mitochondrial variants

that are frequently present at low levels (36–38).

Although the numbers of mitochondria rapidly in-

crease during oogenesis, they maintain a state of re-

latively low activity until the blastocyst stage.

Mitochondria found within oocytes have a morphology

that is more rounded than the typical rod-shaped mor-

phology found in somatic cells, and there are fewer

cristae found in the inner membrane (39). Oocyte mi-

tochondria also have a relatively lower rate of oxygen

consumption, together suggesting that mitochondria

within the oocyte remain in a state of relatively low

activity. It has been hypothesized that the large numbers

of mitochondria functioning at minimal levels are suf-

ficient to provide just the right amount of energy to the

oocyte while minimizing the frequency of mtDNA mu-

tations and the production of ROS (40). This activity is

nonetheless critical for oocyte maturation because gly-

colysis is limited during oogenesis, creating a heavier

reliance on ATP generated by OXPHOS. In addition to

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the energy generated by oocyte mitochondria, energy

transfer from the surrounding granulosa and cumulus

cells, in the form of extracellular pyruvate and glutamine,

also contributes toward the energetic requirements of

oocyte maturation and early embryogenesis (41). The

relatively large numbers of “quiet”mitochondria during

oogenesis further suggests that other functions of mito-

chondria beyond ATP production may be important at

this stage, including the production of the reduced form

of nicotinamide adenine dinucleotide phosphate and

tricarboxylic acid (TCA) cycle intermediates, which may

be used to decrease oxidative stress and provide sub-

strates for other biosynthetic pathways (42).

In addition to dramatic changes in the numbers of

mitochondria during oogenesis, the subcellular locali-

zation of these organelle is remodeled to suit the changing

energy demands of the cell during maturation. The most

significant shift in subcellular localization occurs

when .40% of mitochondria accumulate to surround

the forming meiosis I spindle, remaining with the spindle

during its movement from the oocyte center to the pe-

riphery (43). This association of mitochondria with the

developing spindle is dependent on their trafficking along

microtubules in a dynein-dependent process. Following

the first meiotic division, there is an asymmetric distri-

bution of mitochondria among the daughter cells fa-

voring the oocyte over the polar body, which is of

particular importance given the paucity of mitochondrial

biogenesis from this stage of oogenesis through im-

plantation (44). Mitochondria again associate with the

meiosis II (MII) spindle during its formation; however,

following the completion of the MII spindle formation

and arrest at the MII stage, the mitochondria no longer

completely encase the spindle, but do remain somewhat

enriched in the immediate vicinity (44).

Mutations in Mitochondrial Proteins in POI

Mitochondrial disease represents a group of clinically

heterogeneous disorders that can typically be grouped

together based on their common feature of having a

primary defect in OXPHOS (45). The prevalence of

mitochondrial disease in children is ;6 of 100,000 and in

adults is ;23 of 100,000 (46, 47). Mitochondrial dis-

eases can be caused by mutations in either mtDNA or

nuclear-encoded genes, with mutations in .350 genes

having been reported as a cause (48). The clinical pre-

sentations are varied in their onset, inheritance pattern,

and features, but they are often found in organs with high

energy demands, including the brain, skeletal muscle,

and heart. Frequent features include hypertrophic car-

diomyopathy, heart conduction defects, myopathy,

sensorineural deafness, cerebellar ataxia, epilepsy,

and peripheral neuropathy, among others (49).

Nonsyndromic presentations of mitochondrial disease

include mutations in the 12S rRNA that cause non-

syndromic deafness and certain individuals with Leber

optic atrophy, which is caused by mutations in multiple

genes, that present with visual loss as the only clinical

feature (50, 51). This brings up one of the more per-

plexing features of mitochondrial disorders, which is that

despite the fact that mitochondria are critical for the

function of every cell in the body, their clinical pre-

sentation can often be organ or cell specific. Addition-

ally, not all patients with mitochondrial disease have

OXPHOS defects, as evidenced by patients with TCA

cycle defects due to mutations in aconitase 2 (ACO2)

who present with infantile cerebellar-retinal degen-

eration. ACO2, which catalyzes the conversion of

citrate to isocitrate within the TCA cycle, is not consis-

tently associated with defects in OXPHOS in patient-

derived tissue samples, but rather is characterized by

abnormal TCA metabolite levels and mtDNA depletion

(52–54).

In addition to the frequently observed defects in the

heart, brain, and muscle, the presentation of mitochon-

drial dysfunction often presents with a range of endocrine

features, including diabetes mellitus, GH deficiency,

hypogonadism, thyroid disease, and ovarian dysfunc-

tion, among others (55, 56). Ovarian dysfunction can be

seen as part of a complex syndromic presentation, but it

also includes disorders where it is the only clinical

finding. Mitochondrial mutations that lead to ovarian

dysfunction have been linked to mtDNA, mitochondrial

RNA, and mitochondrial protein synthesis, with func-

tions in multiple distinct biological pathways (57). Much

of what is known about the pathophysiology underlying

ovarian dysfunction has been learned from the identifi-

cation of disease genes identified in rare monogenic

disorders (58). Below is a discussion of eight genes that

when mutated give rise to either isolated POI or POI as

part of a syndrome (Table 1), as well as three additional

genes that have recently been described in a single patient

or family, suggesting a potential link between those genes

and POI as well.

Rare Monogenic Mitochondrial Disorders

Associated With POI

DNA polymerase g, catalytic subunit

DNA polymerase g, catalytic subunit (POLG) is the

catalytic subunit of the mitochondrial DNA polymerase

that is responsible for replication of the mitochondrial

genome (59). Mutations in POLG cause depletion of the

mtDNA and/or the accumulation of deletions in the

mtDNA and are the most commonly inherited form

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of monogenic mitochondrial disease (60). Mutations

in POLG cause a spectrum of disorders, including

myocerebrohepatopathy spectrum, Alpers–Huttenlocher

syndrome, and progressive external ophthalmoplegia,

among others, but they lack a clear cut genotype–

phenotype correlation between the .300 described

pathogenic mutations and the clinical presentation (61).

Among the disparate clinical features associated with

POLG mutations are epilepsy, ataxia, parkinsonism,

hearing loss, cataracts, as well as POI (60, 62). Although

the clinical presentation of POLG mutations can vary,

POI has typically been described as part of a syndrome

including the previously mentioned neurologic features,

and not in isolation (55). However, a recent case report

described identifying the first case of nonsyndromic

ovarian dysfunction associated with a mutation in

POLG (p.R964C), although caution must be taken in

interpreting this study until additional cases are identi-

fied (63). Finally, although candidate gene–based stud-

ies have previously failed to find evidence of POLG

mutations as a common cause of POI (64, 65), a recent

meta–genome-wide association study analysis identified

an association between a single-nucleotide poly-

morphism located near POLG (rs1054875) and the age

at natural menopause, suggesting that variation in

POLG may contribute to the more common polygenic

forms of POI (66).

Twinkle mtDNA helicase

Twinkle mtDNA helicase (TWNK; also known as

C10ORF2) encodes a mitochondrial helicase that to-

gether with the above-mentioned POLG, the DNA

polymerase gaccessory subunit POLG2, and the mi-

tochondrial single-stranded DNA-binding protein

SSBP1 form the core factors required for mtDNA rep-

lication (67, 68). Similar to POLG, mutations in TWNK

can cause a spectrum of genetic disorders, including

progressive external ophthalmoplegia, mtDNA depletion

syndrome 7 (hepatocerebral type), and Perrault syn-

drome, with clinical presentations that can contain

POI in association with other neurologic findings. For

example, 2 unrelated families each had 2 individuals

present with ataxia, neuropathy, hyporeflexia, pro-

gressive hearing loss, and ovarian dysgenesis, with af-

fected individuals in both families found to be compound

heterozygous for missense mutations in TWNK (69).

Given the functional overlap between POLG and TWNK

in mtDNA replication, it is perhaps not surprising that

mutations in both genes can cause a similar constella-

tion of clinical features, including POI, and together

clearly implicates the importance of mtDNA replication in

ovarian development. However, thus far mutations in the

other core components of mtDNA replication, POLG2

and SSBP1, have not been associated with ovarian dys-

function, although mutations have been observed in

POLG2 that, similar to POLG, cause progressive external

ophthalmoplegia (70).

Leucyl-tRNA synthetase 2, mitochondrial and

histidyl-tRNA synthetase 2, mitochondrial

Histidyl-tRNA synthetase 2, mitochondrial (HARS2)

and leucyl-tRNA synthetase 2, mitochondrial (LARS2)

both encode aminoacyl-tRNA synthetases (aaRSs) that

are used for the translation of mitochondrial-encoded

genes. Mitochondrial aaRSs can be categorized into two

major classification groups, class I and class II, based on

their structural motifs, with LARS2 encoding a class I

aaRS based on the presence of a Rossmann fold that

serves as an ATP biding region and HARS2 encoding a

class II aaRS based on three structural motifs referred to

as 1, 2, and 3 (71). Mutations in both HARS2 and

LARS2 are associated with Perrault syndrome, which

Table 1. Mitochondria-Related Genes in Which Mutations Can Cause POI

Gene Inheritance Clinical Presentation Gene Function Molecular Function in Mitochondria

POLG AR, AD Progressive external ophthalmoplegia DNA polymerase mtDNA replication and maintenance

Mitochondrial DNA depletion syndrome

Mitochondrial recessive ataxia syndrome

TWNK AR Perrault syndrome mtDNA helicase mtDNA replication and proofreading

Mitochondrial DNA depletion syndrome

Progressive external ophthalmoplegia

LARS2 AR Perrault syndrome Leucine tRNA mRNA translation

HARS2 AR Perrault syndrome Histidine tRNA mRNA translation

AARS2 AR Ovarioleukodystrophy Alanine tRNA mRNA translation

Combined OXPHOS deficiency

CLPP AR Perrault syndrome Protease Protein degradation

LRPPRC AR Leigh syndrome RNA binding protein Gene expression

MRPS22 AR Isolated POI Ribosomal subunit mRNA translation

Combined OXPHOS deficiency

Abbreviations: AD, autosomal dominant; AR, autosomal recessive.

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describes a rare recessively inherited condition composed

of sensorineural hearing loss in both males and females

and ovarian dysfunction, including ovarian dysgenesis

and primary amenorrhea, and can include neurologic

features including ataxia, learning disability, and neu-

ropathy (72–74). Testicular dysfunction has not been

observed in males with the same mutations that cause

ovarian dysfunction in females (72). However, the

number of deaf males with Perrault syndrome mutations

whose sperm function has been clinically evaluated is

small, and a mouse model of Perrault syndrome due to

complete Clpp deficiency (discussed below) is associated

with infertility in both males and females (75, 76).

Among the 19 mitochondrial aaRSs, it remains unclear

why mutations in these two particular genes result in

hearing loss and ovarian dysfunction, whereas mutations

in other mitochondrial aaRSs result in multiorgan sys-

temic disorders (77). However, although most disease-

causing mutations in aaRSs occur at residues that are not

evolutionarily conserved, mutations in both HARS2 and

LARS2 have been described at conserved positions,

suggesting that the mutations in these genes may similarly

affect the canonical functions of these proteins (78).

Alanyl-tRNA synthetase 2, mitochondrial

Alanyl-tRNA synthetase 2, mitochondrial (AARS2),

similar to HARS2 and LARS, is a mitochondrial aaRS;

however, mutations in AARS2 do not cause Perrault

syndrome, but instead are associated with recessively

inherited ovarioleukodystrophy syndrome in females

(79–83). Mutations in AARS2 have also been linked to

infantile mitochondrial cardiomyopathy and primary

pulmonary hypoplasia resulting in early childhood le-

thality (84, 85). The ovarioleukodystrophy syndrome

consists of neurologic features stemming from neurologic

deterioration, including ataxia, spasticity, tremor, and

cognitive decline, with ages of onset ranging from

childhood to adulthood, in the absence of cardiomyop-

athy. Ovarian failure occurs in the 20s or 30s and has

been reported with both primary amenorrhea or sec-

ondary amenorrhea. AARS2 mutations that lead to in-

fantile cardiomyopathy reduce protein stability with

minimal effects on aminoacylation, whereas the molec-

ular basis underlying the ovarioleukodystrophy syn-

drome remains unknown (86). However, it has been

hypothesized that the ovarioleukodystrophy is associated

with a reduction in aminoacylation efficiency, although

this remains to be experimentally validated (87).

Caseinolytic mitochondrial matrix peptidase

proteolytic subunit

Caseinolytic mitochondrial matrix peptidase pro-

teolytic subunit (CLPP) is an ATP-dependent protease

that is localized to the mitochondrial matrix where, to-

gether with caseinolytic mitochondrial matrix peptidase

chaperone subunit (CLPX), it is part of the quality

control system that degrades oxidized and denatured

proteins (88). A number of CLPP substrates for degra-

dation have been identified and include proteins involved

in electron transport, metabolic processes, the TCA

cycle, and mitochondrial mRNA, among others (89–91).

Consistent with the identified substrates, CLPP de-

ficiency in experimental model systems leads to reduced

mitochondrial respiration, increased ROS, and impaired

mitochondrial protein synthesis associated with defects

in assembly of the mitochondrial ribosome (89, 92).

Mutations in CLPP cause recessively inherited Perrault

syndrome type 3 associated with ovarian dysfunction,

hearing loss, and neurologic defects such as lower limb

spasticity, epilepsy, microcephaly, and learning difficul-

ties (93–96). Functional characterization of the identified

mutations in CLPP resulted in a variety of functional

defects, including decreased peptidase activity, inhibition

of CLPX binding, prevention of oligomerization, and

enhanced peptidase activity, suggesting that despite the

clustering of most CLPP mutations near the CLPX-

docking site or the active site of the peptidase, there

may not be a common defect in the molecular function of

CLPP (97). A mouse knockout of Clpp has also been

generated, which similarly demonstrated hearing loss

and infertility due to the failure of ovarian follicular

differentiation in females, as well as growth retardation,

decreased activity, impaired survival, and disruption of

spermatogenesis in males, providing a model to better

study the cellular and molecular defects associated with

CLPP deficiency (76).

Leucine-rich pentatricopeptide repeat containing

(LRPPRC) is an RNA-binding protein that plays a critical

role in regulating mitochondrial gene expression.

LRPPRC together with the interacting protein SRA stem-

loop interacting RNA binding protein (SLIRP) directly

bind to and coat nearly all mitochondrial mRNAs,

thereby regulating their structure to improve their

translational fidelity and increase their stability (98, 99).

Although SLIRP and LRPPRC both depend on the other

for stability, they also have unique functions within their

complex, with only LRPPRC being required for poly-

adenylation of mitochondrial mRNAs, whereas SLIRP

functions to target mRNAs to the mitochondrial ribosome

(100). Nuclear functions have also been ascribed to

LRPPRC, including as a cofactor for eukaryotic translation

initiation factor 4E (eIF4e) that regulates nuclear export

and translation, and a component of the PGC1atran-

scription regulation complex that controls the expression

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of key metabolic genes such as phosphoenolpyruvate

carboxykinase (PEPCK) and glucose-6-phosphatase

catalytic subunit (G6PC) in addition to genes involved

in mitochondrial biogenesis (101, 102).

Mutations in LRPPRC cause a rare type of Leigh

syndrome referred to as French-Canadian, because most

patients originate from the Saguenay-Lac-Saint-Jean

region of Qu´ebec. A p.A354V founder mutation is

present in this region at a relatively high allele fre-

quency, resulting in an incidence of ;1 of 2000 births

(103–106). Leigh syndrome, French-Canadian variety,

has an autosomal recessive inheritance pattern with

clinical features that include developmental delay,

failure to thrive, characteristic facial features, and hy-

potonia. Patients are at high risk of death due to neu-

rologic or acidotic crises that can be instigated by

triggers, including infection, stress, diet, illness, or ex-

ercise. Although life expectancy is typically ,5years,

patients can survive to adulthood (107). Female patients

who survive until at least adolescence, in addition to the

neurologic features, present with POI, including ele-

vated FSH, small ovaries that lack follicles, and primary

amenorrhea (106). Although LRPPRC clearly has a

significant effect on expression of mtDNA-encoded

genes, caution must be taken when interpreting this

as conclusive support for the role of mitochondrial

dysfunction in POI, given that LRPPRC also regulates

nuclear gene expression.

Mitochondrial ribosomal protein S22

Mitochondrial ribosomal protein S22 (MRPS22) is a

component of the 28S small subunit of the mitochon-

drial ribosome that enables the translation of mtDNA-

encoded polypeptides (108). MRPS22 is also required

for maintaining the stability of the mitochondrial ri-

bosomal complex (109). Mutations in MRPS22 have

been identified to cause autosomal recessive inheritance

of POI (110, 111). Unlike the syndromes mentioned

above, mutations in MRPS22 caused isolated POI in the

absence of other neurologic or other syndromic fea-

tures. Surprisingly, MRPS22 deficiency did not cause

defects in OXPHOS, suggesting that the etiology of POI

was related to the nonbioenergetic functions of mito-

chondria. In Drosophila,germcell–specific deficiency

of the MRPS22 ortholog resulted in infertility,

suggesting a cell-autonomous role for MRPS22 in germ

cell development (110). Mutations in MRPS22, which

are presumably more deleterious to protein function,

have been identified that impair OXPHOS activity and

lead to systemic disease, including cardiomyopathy,

hypotonia, brain abnormalities, and in certain instances

lethality (112–115). Thus, variants in MRPS22 are as-

sociated with a phenotypic spectrum of disorders ranging

from isolated POI to infantile mitochondrial lethal-

ity (110).

Mitochondria-Related Candidate Genes

for POI Identified in Single Families

or Probands

Mitochondrial ribosomal protein S7, protein only

RNase P catalytic subunit, and required for meiotic

nuclear division 1 homolog

Caution must be exercised when interpreting muta-

tions that have thus far been identified in only a single

family, as the sheer number of potentially deleterious

variants present in all individuals makes it difficult to

identify definitively the true causal variants. Nonetheless,

the initial identification and reporting of these mutations

may facilitate other investigators who encounter muta-

tions in those genes and is thus worthwhile. As such,

mutations have been reported in protein-only RNase P

catalytic subunit (PRORP) as a novel cause of Perrault

syndrome (116). A single consanguineous family was

identified with three individuals presenting with senso-

rineural hearing loss and POI that were each homozy-

gous for a missense variant in PRORP (p.A485V).

Functional studies in patient-derived fibroblasts sup-

ported the presence of mitochondrial dysfunction as

evidenced by impaired processing of mitochondrial RNA

transcripts and an accompanying decrease in protein

levels of multiple OXPHOS components (116). Similarly,

another consanguineous family was identified with two

female siblings who presented with congenital sensori-

neural deafness and lactic acidemia. One sibling had a

significantly more severe presentation, including failure

to thrive, hepatomegaly, and hypoglycemia, and ulti-

mately died at 14 years of age. The sibling has hypo-

glycemia in early childhood that resolved, mild learning

difficulties, and was found at age 16 to have POI (117).

Both siblings were homozygous for a mutation in the

mitochondrial ribosomal protein S7 (MRPS7) at a highly

conserved amino acid residue (p.M184V), and functional

studies in patient-derived fibroblasts identified OXPHOS

defects consistent with a mitochondrial disorder (117).

Another study identified a homozygous missense muta-

tion in required for meiotic nuclear division 1 homolog

(RMND1; p.N238S) that had previously been reported

as a disease causing mutation associated with neurologic,

muscle, and kidney defects (118, 119). However, the

proband in this study carrying the RMND1 variant had

the characteristic features of Perrault syndrome, in-

cluding POI that was observed at 10 years of age, as well

as kidney and growth defects (118). Mutations in

RMND1 have previously been associated with defects in

mitochondrial mRNA translation (120, 121). Although

doi: 10.1210/en.2019-00441 https://academic.oup.com/endo 2359

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these studies each describe a strong candidate gene for

POI, with the studies for MRPS7 and PRORP in par-

ticular elegantly combining both genetic and functional

data, caution must be taken until additional patients are

identified to more concretely establish the genotype–

phenotype correlations.

Mitochondrial Dysfunction Associated

With Common POI

Rare monogenic forms of POI have been instrumental

into opening a window into the key genes and pathways

that are important for ovarian function (Fig. 1) (122).

However, with ;1% of women affected by POI, it is

not a rare disorder, and even cumulatively, the rare

monogenic causes of POI fail to account for most cases.

Nonetheless, that so many genes involved in mitochon-

drial function, and mitochondrial mRNA translation in

particular, have been implicated as causes of rare syn-

dromic or isolated POI suggests that this organelle may

be involved in the more common and genetically and

environmentally complex presentations of POI that ac-

count for most cases. Toward this end, pilot studies of

POI patients with no known etiology have identified an

increased frequency of mutations in the mitochondrially

encoded ATP synthase 6 gene (MT-ATP6) and the

mitochondrially encoded cytochrome coxidase I gene

(MT-CO1); however, in both cases the number of patients

screened was small (n 524 cases and n 563 cases, re-

spectively) (123, 124). The need for cautionin interpreting

small studies for a common disease is evident, as the

conclusions linking MT-ATP6 variants to POI have been

called into question, based on potential ancestry differ-

ences between the case and control populations analyzed

in that study (125). In addition to genetic mutations in

mitochondria, elevated levels of ROS and decreased levels

of OXPHOS activity and ATP production in oocytes have

also been correlated with POI, although again these

studies are limited in size (123, 126–128). Interestingly,

treatment of mice with coenzyme Q10, a product of the

TCA cycle that controls multiple aspects of mitochondrial

biology, including transcription and succinate de-

hydrogenase activity, prevented the onset of POI in

both genetic- and aging-based mouse models of POI

(129). Although these preliminary studies are in-

triguing, future studies with increased power and

further studies in model organisms will be needed to

determine whether mitochondrial dysfunction is a

common contributing factor to the onset of POI.

Summary and Future Directions

It is clear from studies of rare monogenic disorders that

functional mitochondria are necessary to prevent ovarian

dysfunction and infertility. However,

larger and better powered studies are

necessary to access the impact and

causal role of dysfunctional mito-

chondria in most cases of POI.

Nonetheless, we have learned a tre-

mendous amount about the genetics

and pathophysiology of POI by

studying the rare disorders in cases

where a disease-causing mutation has

been identified (Fig. 1). These studies,

which have identified mutations in

genes including MRPS22,HARS2,

LARS2,andAARS2, suggest that one

putative therapeutic target for treating

or preventing POI will be to improve

mitochondrial mRNA translation.

Proof-of-principle experiments have

shown that supplementation with L-

cysteine is able to improve OXPHOS

activity in cell lines from a patient

with a genetic defect that impairs mi-

tochondrial mRNA translation (130).

In other cellular studies, overexpression

of mitochondrial tRNAs were able

to correct function defects in mRNA

Figure 1. Molecular functions of mitochondria-related proteins implicated in POI. A cartoon

depicts the various molecular functions in mitochondria of the proteins in which mutations

have been identified that can cause POI.

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translation and cellular respiration (131–134). Treat-

ment with acetyl-L-carnitine has also long been known

to have beneficial effects on mitochondrial function in

vivo, including improved efficiency of mitochondrial

mRNA translation, and has been proposed as a treat-

ment of a variety of mitochondrial disorders (135).

Treatment with acetyl-L-carnitine improves in vitro

maturation of oocytes and reduces the number of ab-

normal mitochondria, although it is unclear what mo-

lecular mechanism underlies these improvements and

whether these finding will translate to in vivo treatment

or prevention of POI (136–138). These studies have

shown that it is possible to manipulate the mitochon-

drial mRNA translational machinery, although it re-

mains to be seen whether this can be accomplished on a

therapeutic basis and what, if any, clinical benefits

would be seen.

The discoveries that mutations in the mitochondria-

related genes described above and in Table 1 can cause

POI were largely made possible by advances in DNA

sequencing technologies that greatly reduced the cost of

whole-exome sequencing (WES) (139). The initial studies

linking mutations in 8 of the 11 genes to POI used WES in

the process of identifying the causal variant. However,

given the rarity of mutations in these genes as a cause of

POI, the current guidelines for diagnosing and treating

nonsyndromic POI do not recommend testing for mu-

tations in these genes or other monogenic causes of POI

(140). Nonetheless, this may change as WES analyses

continue to become more integrated into routine clinical

practice. There is mounting evidence from numerous

clinical settings demonstrating benefits in terms of both

cost reductions and improved clinical care by in-

corporating WES early into the diagnostic process

(141–146). However, to make this a clinical reality for

POI, more accurate predictions of whether variants are

likely to be pathogenic will be required. Fortunately,

progress can be made toward this end with limited

sample sizes. The studies utilizing WES discussed above

were each based on analyses of individuals with POI from

just one to three families, illustrating the progress that

can result from even small-scale studies.

Despite all that we have learned, many pressing

questions remain unanswered. (i) Why do mutations in

the genes described above cause POI, whereas mutations

in many more related mitochondrial genes do not? (ii)

Why do mutations in genes such as MRPS22 cause a

spectrum of disorders, ranging from isolated POI to

multiorgan systemic disease, and can we predict the

genotype–phenotype correlations? (iii) Why does mito-

chondrial dysfunction preferentially affect the ovary? (iv)

Is mitochondria-associated POI due to cell-autonomous

defects in the oocyte, or rather defects in ovarian somatic

cells or other systemic changes? (v) Is ovarian dysfunction

in rare monogenic cases of POI strictly due to impaired

cellular respiration or are there nonbioenergetic defects

that underlie the disorder? Answers to these questions

will provide insight into the underlying pathophysiology

of POI and may identify new therapeutic targets to im-

prove the diagnosis and treatment of POI.

Acknowledgments

Financial Support: This work was supported by National

Institute of Diabetes and Digestive and Kidney Diseases Grant

DK112846 (to D.A.B.).

Additional Information

Correspondence: David A. Buchner, PhD, Case Western

Reserve University School of Medicine, 10900 Euclid Avenue,

Cleveland, Ohio 44106. E-mail: david.buchner@case.edu;or

Dov Tiosano, MD, Division of Pediatric Endocrinology, Ruth

Rappaport Children’s Hospital, Rambam Medical Center,

HaAliya HaShniya Street 8, Haifa 3109601, Israel. E-mail:

d_tiosano@rambam.health.gov.il.

Disclosure Summary: The authors have nothing to

disclose.

Data Availability: Data sharing is not applicable to this

article as no datasets were generated or analyzed during the

current study.

References and Notes

1. Santoro NF, Cooper AR, eds. Primary Ovarian Insufficiency.

Cham, Switzerland: Springer International Publishing; 2016.

https://doi.org/10.1007/978-3-319-22491-6

2. Cox L, Liu JH. Primary ovarian insufficiency: an update. Int J

Womens Health. 2014;6:235–243.

3. Allshouse AA, Semple AL, Santoro NF. Evidence for prolonged

and unique amenorrhea-related symptoms in women with pre-

mature ovarian failure/primary ovarian insufficiency. Menopause.

2015;22(2):166–174.

4. Christ JP, Gunning MN, Palla G, Eijkemans MJC, Lambalk CB,

Laven JS, Fauser BC. Estrogen deprivation and cardiovascular

disease risk in primary ovarian insufficiency. Fertil Steril. 2018;

109(4):594–600.e1.

5. Podfigurna-Stopa A, Czyzyk A, Grymowicz M, Smolarczyk R,

Katulski K, Czajkowski K, Meczekalski B. Premature ovarian

insufficiency: the context of long-term effects. J Endocrinol Invest.

2016;39(9):983–990.

6. Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary

ovarian insufficiency. Clin Genet. 2017;91(2):183–198.

7. Silva CA, Yamakami LY, Aikawa NE, Araujo DB, Carvalho JF,

Bonf´a E. Autoimmune primary ovarian insufficiency. Autoimmun

Rev. 2014;13(4–5):427–430.

8. Tucker EJ, Jaillard S, Sinclair AH. Genetics and genomics of pri-

mary ovarian insufficiency. In: Leung PC, Qiao J, eds. Human

Reproductive andPrenatal Genetics. San Diego, CA: Elsevier; 2019:

427–445. https://doi.org/10.1016/B978-0-12-813570-9.00019-X

9. Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins:

from biogenesis to functional networks. Nat Rev Mol Cell Biol.

2019;20(5):267–284.

doi: 10.1210/en.2019-00441 https://academic.oup.com/endo 2361

Downloaded from https://academic.oup.com/endo/article/160/10/2353/5544515 by guest on 12 June 2023

10. Picard M, Wallace DC, Burelle Y. The rise of mitochondria in

medicine. Mitochondrion. 2016;30:105–116.

11. Dan Dunn J, Alvarez LA, Zhang X, Soldati T. Reactive oxygen

species and mitochondria: a nexus of cellular homeostasis. Redox

Biol. 2015;6:472–485.

12. Larsson NG. Somatic mitochondrial DNA mutations in mam-

malian aging. Annu Rev Biochem. 2010;79(1):683–706.

13. Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis

and clearance: a balancing act. FEBS J. 2017;284(2):183–195.

14. Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R,

Petcherski A, Ruonala MO, Priault M, Salin B, Reichert AS.

Mitophagy is triggered by mild oxidative stress in a mitochondrial

fission dependent manner. Biochim Biophys Acta. 2012;

1823(12):2297–2310.

15. Kulikov AV, Luchkina EA, Gogvadze V, Zhivotovsky B.

Mitophagy: link to cancer development and therapy. Biochem

Biophys Res Commun. 2017;482(3):432–439.

16. Tandler B, Hoppel CL, Mears JA. Morphological pathways of

mitochondrial division. Antioxidants. 2018;7(2):E30.

17. Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of

nutrient utilization and energy expenditure. Cell Metab. 2013;

17(4):491–506.

18. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J. Tu-

bular network formation protects mitochondria from autopha-

gosomal degradation during nutrient starvation. Proc Natl Acad

Sci USA. 2011;108(25):10190–10195.

19. Wikstrom JD, Mahdaviani K, Liesa M, Sereda SB, Si Y, Las G,

Twig G, Petrovic N, Zingaretti C, Graham A, Cinti S, Corkey BE,

Cannon B, Nedergaard J, Shirihai OS. Hormone-induced mito-

chondrial fission is utilized by brown adipocytes as an amplifi-

cation pathway for energy expenditure. EMBO J. 2014;33(5):

418–436.

20. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Los´on OC,

Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ.

AMP-activated protein kinase mediates mitochondrial fission in

response to energy stress. Science. 2016;351(6270):275–281.

21. Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A,

Walzer G, Twig G, Katz S, Corkey BE, Shirihai OS. Mitochondrial

networking protects b-cells from nutrient-induced apoptosis.

Diabetes. 2009;58(10):2303–2315.

22. Mishra P, Chan DC. Metabolic regulation of mitochondrial dy-

namics. J Cell Biol. 2016;212(4):379–387.

23. Stocco DM. StAR protein and the regulation of steroid hormone

biosynthesis. Annu Rev Physiol. 2001;63(1):193–213.

24. Chien Y, Rosal K, Chung BC. Function of CYP11A1 in the mi-

tochondria. Mol Cell Endocrinol. 2017;441:55–61.

25. Takae S, Suzuki N. Ovarian endocrinology. In: Chian RC,

Nargund G, Huang JYJ, eds. Development of In Vitro Maturation

for Human Oocytes. Cham, Switzerland: Springer International

Publishing; 2017:3–35.

26. S´anchez F, Smitz J. Molecular control of oogenesis. Biochimica

et Biophysica Acta (BBA) - Molecular Basis of Disease. 2012;

1822(12):1896–1912.

27. Gondos B, Westergaard L, Byskov AG. Initiation of oogenesis in

the human fetal ovary: ultrastructural and squash preparation

study. Am J Obstet Gynecol. 1986;155(1):189–195.

28. Pepling ME, Spradling AC. Mouse ovarian germ cell cysts un-

dergo programmed breakdown to form primordial follicles. Dev

Biol. 2001;234(2):339–351.

29. Pepling ME, Wilhelm JE, O’Hara AL, Gephardt GW, Spradling

AC. Mouse oocytes within germ cell cysts and primordial follicles

contain a Balbiani body. Proc Natl Acad Sci USA. 2007;104(1):

187–192.

30. Lei L, Spradling AC. Mouse oocytes differentiate through or-

ganelle enrichment from sister cyst germ cells. Science. 2016;

352(6281):95–99.

31. Rimon-Dahari N, Yerushalmi-Heinemann L, Alyagor L, Dekel N.

Ovarian folliculogenesis. In: Piprek RP, ed. Molecular Mechanisms

of Cell Differentiation in Gonad Development. Vol. 58. Cham,

Switzerland: Springer International Publishing; 2016:167–190.

32. Magoffin DA. Ovarian theca cell. Int J Biochem Cell Biol. 2005;

37(7):1344–1349.

33. Reddy P, Zheng W, Liu K. Mechanisms maintaining the dor-

mancy and survival of mammalian primordial follicles. Trends

Endocrinol Metab. 2010;21(2):96–103.

34. Poulton J, Marchington DR. Segregation of mitochondrial DNA

(mtDNA) in human oocytes and in animal models of mtDNA

disease: clinical implications. Reproduction. 2002;123(6):

751–755.

35. Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T,

Hayashi J, Yonekawa H. The mitochondrial bottleneck occurs

without reduction of mtDNA content in female mouse germ cells.

Nat Genet. 2007;39(3):386–390.

36. Chen D, Clark AT. Mitochondrial DNA selection in human germ

cells. Nat Cell Biol. 2018;20(2):118–120.

37. Floros VI, Pyle A, Dietmann S, Wei W, Tang WCW, Irie N, Payne

B, Capalbo A, Noli L, Coxhead J, Hudson G, Crosier M, Strahl H,

Khalaf Y, Saitou M, Ilic D, Surani MA, Chinnery PF. Segregation

of mitochondrial DNA heteroplasmy through a developmental

genetic bottleneck in human embryos [published correction ap-

pears in Nat Cell Biol. 2018;20(8):991]. Nat Cell Biol. 2018;

20(2):144–151.

38. Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL,

Bennett DL, Gale DP, Bitner-Glindzicz MA, Black GC, Brennan P,

Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A,

Maher ER, Markus HS, Morrell NW, Newman WG, Roberts I,

Sayer JA, Smith KG, Taylor JC, Watkins H, Webster AR, Wilkie

AO, Williamson C, Ashford S, Penkett CJ, Stirrups KE, Rendon A,

Ouwehand WH, Bradley JR, Raymond FL, Caulfield M, Turro E,

Chinnery PF; NIHR BioResource—Rare Diseases; 100,000 Ge-

nomes Project—Rare Diseases Pilot. Germline selection shapes

human mitochondrial DNA diversity. Science. 2019;364(6442):

eaau6520.

39. de Paula WB, Lucas CH, Agip AN, Vizcay-Barrena G, Allen JF.

Energy, ageing, fidelity and sex: oocyte mitochondrial DNA as a

protected genetic template. Philos Trans R Soc Lond B Biol Sci.

2013;368(1622):20120263.

40. Leese HJ, Guerif F, Allgar V, Brison DR, Lundin K, Sturmey RG.

Biological optimization, the Goldilocks principle, and how much

is lagom in the preimplantation embryo. Mol Reprod Dev. 2016;

83(9):748–754.

41. Collado-Fernandez E, Picton HM, Dumollard R. Metabolism

throughout follicle and oocyte development in mammals. Int J

Dev Biol. 2012;56(10–12):799–808.

42. Dumollard R, Carroll J, Duchen MR, Campbell K, Swann K.

Mitochondrial function and redox state in mammalian embryos.

Semin Cell Dev Biol. 2009;20(3):346–353.

43. Coticchio G, Dal Canto M, Mignini Renzini M, Guglielmo MC,

Brambillasca F, Turchi D, Novara PV, Fadini R. Oocyte matu-

ration: gamete-somatic cells interactions, meiotic resumption,

cytoskeletal dynamics and cytoplasmic reorganization. Hum

Reprod Update. 2015;21(4):427–454.

44. Dalton CM, Carroll J. Biased inheritance of mitochondria during

asymmetric cell division in the mouse oocyte. J Cell Sci. 2013;

126(Pt 13):2955–2964.

45. Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing

mitochondrial disease: What is new and what challenges remain?

Science. 2015;349(6255):1494–1499.

46. Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston

CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor

RW, Turnbull DM, McFarland R. Prevalence of nuclear and

mitochondrial DNA mutations related to adult mitochondrial

disease. Ann Neurol. 2015;77(5):753–759.

47. Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence

of mitochondrial respiratory chain disorders in children. Brain.

2003;126(Pt 8):1905–1912.

2362 Tiosano et al Mitochondrial Dysfunction in POI Endocrinology, October 2019, 160(10):2353–2366

Downloaded from https://academic.oup.com/endo/article/160/10/2353/5544515 by guest on 12 June 2023

48. Rahman J, Rahman S. Mitochondrial medicine in the omics era.

Lancet. 2018;391(10139):2560–2574.

49. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The

genetics and pathology of mitochondrial disease. J Pathol. 2017;

241(2):236–250.

50. Prezant TR, Agapian JV, Bohlman MC, Bu X, ¨

Oztas S, Qiu WQ,

Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Fischel-

Ghodsian N. Mitochondrial ribosomal RNA mutation associated

with both antibiotic-induced and non-syndromic deafness. Nat

Genet. 1993;4(3):289–294.

51. Wallace DC, Lott MT. Leber hereditary optic neuropathy: ex-

emplar of an mtDNA disease. In: Singh H, Sheu SS, eds. Phar-

macology of Mitochondria. Vol. 240. Cham, Switzerland:

Springer International Publishing; 2017:339–376.

52. Abela L, Spiegel R, Crowther LM, Klein A, Steindl K, Papuc SM,

Joset P, Zehavi Y, Rauch A, Plecko B, Simmons TL. Plasma

metabolomics reveals a diagnostic metabolic fingerprint for mi-

tochondrial aconitase (ACO2) deficiency. PLoS One. 2017;12(5):

e0176363.

53. Sadat R, Barca E, Masand R, Donti TR, Naini A, De Vivo DC,

DiMauro S, Hanchard NA, Graham BH. Functional cellular

analyses reveal energy metabolism defect and mitochondrial DNA

depletion in a case of mitochondrial aconitase deficiency. Mol

Genet Metab. 2016;118(1):28–34.

54. Spiegel R, Pines O, Ta-Shma A, Burak E, Shaag A, Halvardson J,

Edvardson S, Mahajna M, Zenvirt S, Saada A, Shalev S, Feuk L,

Elpeleg O. Infantile cerebellar-retinal degeneration associated

with a mutation in mitochondrial aconitase, ACO2.Am J Hum

Genet. 2012;90(3):518–523.

55. Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S.

Mitochondrial disease and endocrine dysfunction. Nat Rev

Endocrinol. 2017;13(2):92–104.

56. Al-Gadi IS, Haas RH, Falk MJ, Goldstein A, McCormack SE.

Endocrine disorders in primary mitochondrial disease. J Endocr

Soc. 2018;2(4):361–373.

57. Demain LA, ConwayGS, NewmanWG. Genetics of mitochondrial

dysfunction and infertility. Clin Genet. 2017;91(2):199–207.

58. Koopman WJ, Willems PH, Smeitink JA. Monogenic mito-

chondrial disorders. N Engl J Med. 2012;366(12):1132–1141.

59. Ropp PA, Copeland WC. Cloning and characterization of the

human mitochondrial DNA polymerase, DNA polymerase

gamma. Genomics. 1996;36(3):449–458.

60. Rahman S, Copeland WC. POLG-related disorders and their

neurological manifestations. Nat Rev Neurol. 2019;15(1):40–52.

61. Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC.

Consequences of mutations in human DNA polymerase gamma.

Gene. 2005;354:125–131.

62. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN,

Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L, Majamaa K,

Somer H, Suomalainen A. Parkinsonism, premature menopause,

and mitochondrial DNA polymerase gmutations: clinical and

molecular genetic study. Lancet. 2004;364(9437):875–882.

63. Chen B, Li L, Wang J, Zhou Y, Zhu J, Li T, Pan H, Liu B, Cao Y,

Wang B. Identification of the first homozygous POLG mutation

causing non-syndromic ovarian dysfunction. Climacteric. 2018;

21(5):467–471.

64. Tong ZB, Sullivan SD, Lawless LM, Vanderhoof V, Zachman K,

Nelson LM. Five mutations of mitochondrial DNA polymerase-

gamma (POLG) are not a prevalent etiology for spontaneous

46,XX primary ovarian insufficiency. Fertil Steril. 2010;94(7):

2932–2934.

65. Duncan AJ, Knight JA, Costello H, Conway GS, Rahman S.

POLG mutations and age at menopause. Hum Reprod. 2012;

27(7):2243–2244.

66. Day FR, Ruth KS, Thompson DJ, Lunetta KL, Pervjakova N,

Chasman DI, Stolk L, Finucane HK, Sulem P, Bulik-Sullivan B,

Esko T, Johnson AD, Elks CE, Franceschini N, He C, Altmaier E,

Brody JA, Franke LL, Huffman JE, Keller MF, McArdle PF, Nutile

T, Porcu E, Robino A, Rose LM, Schick UM, Smith JA, Teumer A,

Traglia M, Vuckovic D, Yao J, Zhao W, Albrecht E, Amin N,

Corre T, Hottenga JJ, Mangino M, Smith AV, Tanaka T, Abecasis

GR, Andrulis IL, Anton-Culver H, Antoniou AC, Arndt V, Arnold

AM, Barbieri C, Beckmann MW, Beeghly-Fadiel A, Benitez J,

Bernstein L, Bielinski SJ, Blomqvist C, Boerwinkle E, Bogdanova

NV, Bojesen SE, Bolla MK, Borresen-Dale AL, Boutin TS, Brauch

H, Brenner H, Br ¨uning T, Burwinkel B, Campbell A, Campbell H,

Chanock SJ, Chapman JR, Chen YD, Chenevix-Trench G, Couch

FJ, Coviello AD, Cox A, Czene K, Darabi H, De Vivo I, Demerath

EW, Dennis J, Devilee P, D ¨ork T, dos-Santos-Silva I, Dunning

AM, Eicher JD, Fasching PA, Faul JD, Figueroa J, Flesch-Janys D,

Gandin I, Garcia ME, Garc´

ıa-Closas M, Giles GG, Girotto GG,

Goldberg MS, Gonz´alez-Neira A, Goodarzi MO, Grove ML,

Gudbjartsson DF, Gu´enel P, Guo X, Haiman CA, Hall P, Hamann

U, Henderson BE, Hocking LJ, Hofman A, Homuth G, Hooning

MJ, Hopper JL, Hu FB, Huang J, Humphreys K, Hunter DJ,

Jakubowska A, Jones SE, Kabisch M, Karasik D, Knight JA,

Kolcic I, Kooperberg C, Kosma VM, Kriebel J, Kristensen V,

Lambrechts D, Langenberg C, Li J, Li X, Lindstr ¨om S, Liu Y, Luan

J, Lubinski J, M¨agi R, Mannermaa A, Manz J, Margolin S,

Marten J, Martin NG, Masciullo C, Meindl A, Michailidou K,

Mihailov E, Milani L, Milne RL, M ¨uller-Nurasyid M, Nalls M,

Neale BM, Nevanlinna H, Neven P, Newman AB, Nordestgaard

BG, Olson JE, Padmanabhan S, Peterlongo P, Peters U,

Petersmann A, Peto J, Pharoah PD, Pirastu NN, Pirie A, Pistis G,

Polasek O, Porteous D, Psaty BM, Pylk ¨as K, Radice P, Raffel LJ,

Rivadeneira F, Rudan I, Rudolph A, Ruggiero D, Sala CF, Sanna

S, Sawyer EJ, Schlessinger D, Schmidt MK, Schmidt F, Schmutzler

RK, Schoemaker MJ, Scott RA, Seynaeve CM, Simard J, Sorice R,

Southey MC, St ¨ockl D, Strauch K, Swerdlow A, Taylor KD,

Thorsteinsdottir U, Toland AE, Tomlinson I, Truong T,

Tryggvadottir L, Turner ST, Vozzi D, Wang Q, Wellons M,

Willemsen G, Wilson JF, Winqvist R, Wolffenbuttel BB, Wright

AF, Yannoukakos D, Zemunik T, Zheng W, Zygmunt M,

Bergmann S, Boomsma DI, Buring JE, Ferrucci L, Montgomery

GW, Gudnason V, Spector TD, van Duijn CM, Alizadeh BZ,

Ciullo M, Crisponi L, Easton DF, Gasparini PP, Gieger C, Harris

TB, Hayward C, Kardia SL, Kraft P, McKnight B, Metspalu A,

Morrison AC, Reiner AP, Ridker PM, Rotter JI, Toniolo D,

Uitterlinden AG, Ulivi S, V ¨olzke H, Wareham NJ, Weir DR,

Yerges-Armstrong LM, Price AL, Stefansson K, Visser JA, Ong

KK, Chang-Claude J, Murabito JM, Perry JR, Murray A;

PRACTICAL Consortium; kConFab Investigators; AOCS In-

vestigators; Generation Scotland; EPIC-InterAct Consortium;

LifeLines Cohort Study. Large-scale genomic analyses link re-

productive aging to hypothalamic signaling, breast cancer sus-

ceptibility and BRCA1-mediated DNA repair. Nat Genet. 2015;

47(11):1294–1303.

67. Suomalainen A, Battersby BJ. Mitochondrial diseases: the con-

tribution of organelle stress responses to pathology. Nat Rev Mol

Cell Biol. 2018;19(2):77–92.

68. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. Re-

constitution of a minimal mtDNA replisome in vitro. EMBO J.

2004;23(12):2423–2429.

69. Morino H, Pierce SB, Matsuda Y, Walsh T, Ohsawa R, Newby M,

Hiraki-Kamon K, Kuramochi M, Lee MK, Klevit RE, Martin A,

Maruyama H, King MC, Kawakami H. Mutations in Twinkle

primase-helicase cause Perrault syndrome with neurologic fea-

tures. Neurology. 2014;83(22):2054–2061.

70. Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE,

Taylor RW, Nightingale S, Turnbull DM, Copeland WC,

Chinnery PF. Mutant POLG2 disrupts DNA polymerase g

subunits and causes progressive external ophthalmoplegia. Am J

Hum Genet. 2006;78(6):1026–1034.

71. Suzuki T, Nagao A, Suzuki T. Human mitochondrial tRNAs:

biogenesis, function, structural aspects, and diseases. Annu Rev

Genet. 2011;45(1):299–329.

doi: 10.1210/en.2019-00441 https://academic.oup.com/endo 2363

Downloaded from https://academic.oup.com/endo/article/160/10/2353/5544515 by guest on 12 June 2023

72. Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK,

Malach D, Klevit RE, King MC, Levy-Lahad E. Mutations in

LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to

premature ovarian failure and hearing loss in Perrault syndrome.

Am J Hum Genet. 2013;92(4):614–620.

73. Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM,

Li W, Klevit RE, King MC. Mutations in mitochondrial histidyl

tRNA synthetase HARS2 cause ovarian dysgenesis and sensori-

neural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA.

2011;108(16):6543–6548.

74. Kosaki R, Horikawa R, Fujii E, Kosaki K. Biallelic mutations in

LARS2 can cause Perrault syndrome type 2 with neurologic

symptoms. Am J Med Genet A. 2018;176(2):404–408.

75. Rehman AU, Friedman TB, Griffith AJ. Unresolved questions

regarding human hereditary deafness. Oral Dis. 2017;23(5):

551–558.

76. Gispert S, Parganlija D, Klinkenberg M, Dr¨ose S, Wittig I,

Mittelbronn M, Grzmil P, Koob S, Hamann A, Walter M, B ¨uchel

F, Adler T, Hrab´e de Angelis M, Busch DH, Zell A, Reichert AS,

Brandt U, Osiewacz HD, Jendrach M, Auburger G. Loss of mi-

tochondrial peptidase Clpp leads to infertility, hearing loss plus

growth retardation via accumulation of CLPX, mtDNA and in-

flammatory factors. Hum Mol Genet. 2013;22(24):4871–4887.

77. Gonz´alez-Serrano LE, Chihade JW, Sissler M. When a common

biological role does not imply common disease outcomes: dis-

parate pathology linked to human mitochondrial aminoacyl-

tRNA synthetases. J Biol Chem. 2019;294(14):5309–5320.

78. Sissler M, Gonz´alez-Serrano LE, Westhof E. Recent advances in

mitochondrial aminoacyl-tRNA synthetases and disease. Trends

Mol Med. 2017;23(8):693–708.

79. Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ,

Salomons GS, Baruffini E, Melchionda L, Mariotti C, Strom TM,

Meitinger T, Prokisch H, Chapman K, Colley A, Rocha H, Ounap

K, Schiffmann R, Salsano E, Savoiardo M, Hamilton EM, Abbink

TE, Wolf NI, Ferrero I, Lamperti C, Zeviani M, Vanderver A,

Ghezzi D, van der Knaap MS. Novel (ovario) leukodystrophy

related to AARS2 mutations. Neurology. 2014;82(23):

2063–2071.

80. Lynch DS, Zhang WJ, Lakshmanan R, Kinsella JA, Uzun GA,

Karbay M, T ¨ufekçioglu Z, Hanagasi H, Burke G, Foulds N,

Hammans SR, Bhattacharjee A, Wilson H, Adams M, Walker M,

Nicoll JA, Chataway J, Fox N, Davagnanam I, Phadke R,

Houlden H. Analysis of mutations in AARS2 in a Series of CSF1R-

negative patients with adult-onset leukoencephalopathy with

axonal spheroids and pigmented glia. JAMA Neurol. 2016;

73(12):1433–1439.

81. Taglia I, Di Donato I, Bianchi S, Cerase A, Monti L, Marconi R,

Orrico A, Rufa A, Federico A, Dotti MT. AARS2-related ovar-

ioleukodystrophy: clinical and neuroimaging features of three new

cases. Acta Neurol Scand. 2018;138(4):278–283.

82. Hamatani M, Jingami N, Tsurusaki Y, Shimada S, Shimojima K,

Asada-Utsugi M, Yoshinaga K, Uemura N, Yamashita H, Uemura

K, Takahashi R, Matsumoto N, Yamamoto T. The first Japanese

case of leukodystrophy with ovarian failure arising from novel

compound heterozygous AARS2 mutations. J Hum Genet. 2016;

61(10):899–902.

83. Lee JM, Yang HJ, Kwon JH, Kim WJ, Kim SY, Lee EM, Park JY,

Weon YC, Park SH, Gwon BJ, Ryu JC, Lee ST, Kim HJ, Jeon B.

Two Koreansiblings with recently described ovarioleukodystrophy

related to AARS2 mutations. Eur J Neurol.2017;24(4):e21–e22.

84. Kiraly-Borri C, Jevon G, Ji W, Jeffries L, Ricciardi J-L,

Konstantino M, Ackerman KG, Lakhani SA. Siblings with lethal

primary pulmonary hypoplasia and compound heterozygous

variants in the AARS2 gene: further delineation of the phenotypic

spectrum. Cold Spring Harb Mol Case Stud. 2019;5(3):a003699.

85. G¨otz A, Tyynismaa H, Euro L, Ellonen P, Hy ¨otyl¨ainen T, Ojala T,

H¨am ¨al¨ainen RH, Tommiska J, Raivio T, Oresic M, Karikoski R,

Tammela O, Simola KOJ, Paetau A, Tyni T, Suomalainen A. Exome

sequencing identifies mitochondrial alanyl-tRNA synthetase mutations

in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011;

88(5):635–642.

86. Sommerville EW, Zhou X-L, Ol ´ahov´a M, Jenkins J, Euro L,

Konovalova S, Hilander T, Pyle A, He L, Habeebu S, Saunders C,

Kelsey A, Morris AAM, McFarland R, Suomalainen A, Gorman

GS, Wang ED, Thiffault I, Tyynismaa H, Taylor RW. Instability

of the mitochondrial alanyl-tRNA synthetase underlies fatal

infantile-onset cardiomyopathy. Hum Mol Genet. 2019;28(2):

258–268.

87. Euro L, Konovalova S, Asin-Cayuela J, Tulinius M, Griffin H,

Horvath R, Taylor RW, Chinnery PF, Schara U, Thorburn DR,

Suomalainen A, Chihade J, Tyynismaa H. Structural modeling of

tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2)

defects predicts differential effects on aminoacylation. Front

Genet. 2015;6:21.

88. Fischer F, Hamann A, Osiewacz HD. Mitochondrial quality

control: an integrated network of pathways. Trends Biochem Sci.

2012;37(7):284–292.

89. Szczepanowska K, Maiti P, Kukat A, Hofsetz E, Nolte H, Senft K,

Becker C, Ruzzenente B, Hornig-Do HT, Wibom R, Wiesner RJ,

Kr ¨uger M, Trifunovic A. CLPP coordinates mitoribosomal as-

sembly through the regulation of ERAL1 levels. EMBO J. 2016;

35(23):2566–2583.

90. Cole A, Wang Z, Coyaud E, Voisin V, Gronda M, Jitkova Y,

Mattson R, Hurren R, Babovic S, Maclean N, Restall I, Wang X,

Jeyaraju DV, Sukhai MA, Prabha S, Bashir S, Ramakrishnan A,

Leung E, Qia YH, Zhang N, Combes KR, Ketela T, Lin F, Houry

WA, Aman A, Al-Awar R, Zheng W, Wienholds E, Xu CJ, Dick J,

Wang JC, Moffat J, Minden MD, Eaves CJ, Bader GD, Hao Z,

Kornblau SM, Raught B, Schimmer AD. Inhibition of the mito-

chondrial protease ClpP as a therapeutic strategy for human acute

myeloid leukemia. Cancer Cell. 2015;27(6):864–876.

91. Fischer F, Langer JD, Osiewacz HD. Identification of potential

mitochondrial CLPXP protease interactors and substrates sug-

gests its central role in energy metabolism. Sci Rep. 2015;5(1):

18375.

92. Deepa SS, Bhaskaran S, Ranjit R, Qaisar R, Nair BC, Liu Y, Walsh

ME, Fok WC, Van Remmen H. Down-regulation of the mito-

chondrial matrix peptidase ClpP in muscle cells causes mito-

chondrial dysfunction and decreases cell proliferation. Free Radic

Biol Med. 2016;91:281–292.

93. Lerat J, Jonard L, Loundon N, Christin-Maitre S, Lacombe D,

Goizet C, Rouzier C, Van Maldergem L, Gherbi S, Garabedian

EN, Bonnefont JP, Touraine P, Mosnier I, Munnich A, Denoyelle

F, Marlin S. An application of NGS for molecular investigations in

Perrault syndrome: study of 14 families and review of the liter-

ature. Hum Mutat. 2016;37(12):1354–1362.

94. Dursun F, Mohamoud HSA, Karim N, Naeem M, Jelani M,

Kırmızıbekmez H. A novel missense mutation in the CLPP gene

causing Perrault Syndrome type 3 in a Turkish family. J Clin Res

Pediatr Endocrinol. 2016;8(4):472–477.

95. Ahmed S, Jelani M, Alrayes N, Mohamoud HS, Almramhi MM,

Anshasi W, Ahmed NA, Wang J, Nasir J, Al-Aama JY. Exome

analysis identified a novel missense mutation in the CLPP gene

in a consanguineous Saudi family expanding the clinical spectrum

of Perrault syndrome type-3. J Neurol Sci. 2015;353(1–2):

149–154.

96. Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K,

Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B,

Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley

NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ,

Warner TT, Black GC, Trump D, Davis JR, Ahmad W, Leal SM,

Riazuddin S, King MC, Friedman TB, Newman WG; University of

Washington Center for Mendelian Genomics. Perrault syndrome

is caused by recessive mutations in CLPP, encoding a mito-

chondrial ATP-dependent chambered protease. Am J Hum Genet.

2013;92(4):605–613.

2364 Tiosano et al Mitochondrial Dysfunction in POI Endocrinology, October 2019, 160(10):2353–2366

Downloaded from https://academic.oup.com/endo/article/160/10/2353/5544515 by guest on 12 June 2023

97. Brodie EJ, Zhan H, Saiyed T, Truscott KN, Dougan DA. Perrault

syndrome type 3 caused by diverse molecular defects in CLPP. Sci

Rep. 2018;8(1):12862.

98. Siira SJ, Sp˚ahr H, Shearwood AJ, Ruzzenente B, Larsson NG,

Rackham O, Filipovska A. LRPPRC-mediated folding of the

mitochondrial transcriptome. Nat Commun. 2017;8(1):1532.

99. Ruzzenente B, Metodiev MD, Wredenberg A, Bratic A, Park CB,

C´amara Y, Milenkovic D, Zickermann V, Wibom R, Hultenby K,

Erdjument-Bromage H, Tempst P, Brandt U, Stewart JB,

Gustafsson CM, Larsson NG. LRPPRC is necessary for poly-

adenylation and coordination of translation of mitochondrial

mRNAs. EMBO J. 2012;31(2):443–456.

100. Lagouge M, Mourier A, Lee HJ, Sp ˚ahr H, Wai T, Kukat C, Silva

Ramos E, Motori E, Busch JD, Siira S, Kremmer E, Filipovska A,

Larsson NG; German Mouse Clinic Consortium. SLIRP regulates

the rate of mitochondrial protein synthesis and protects LRPPRC

from degradation. PLoS Genet. 2015;11(8):e1005423.

101. Volpon L, Culjkovic-Kraljacic B, Sohn HS, Blanchet-Cohen A,

Osborne MJ, Borden KL. A biochemical framework for eIF4E-

dependent mRNA export and nuclear recycling of the export

machinery. RNA. 2017;23(6):927–937.

102. Cooper MP, Qu L, Rohas LM, Lin J, Yang W, Erdjument-

Bromage H, Tempst P, Spiegelman BM. Defects in energy ho-

meostasis in Leigh syndrome French Canadian variant through

PGC-1a/LRP130 complex. Genes Dev. 2006;20(21):2996–3009.

103. Han VX, TanTS, Wang FS, Tay SK. NovelLRPPRC mutation in a

boy with mild Leigh syndrome, French–Canadian type outside of

Qu´ebec. Child Neurol Open. 2017;4: 2329048X17737638. doi:

10.1177/2329048X17737638.

104. Ol´ahov ´a M, Hardy SA, Hall J, Yarham JW, Haack TB, Wilson

WC, Alston CL, He L, Aznauryan E, Brown RM, Brown GK,

Morris AAM, Mundy H, Broomfield A, Barbosa IA, Simpson

MA, Deshpande C, Moeslinger D, Koch J, Stettner GM, Bonnen

PE, Prokisch H, Lightowlers RN, McFarland R, Chrzanowska-

Lightowlers ZM, Taylor RW. LRPPRC mutations cause early-onset

multisystem mitochondrial disease outside of the French-Canadian

population. Brain. 2015;138(Pt 12):3503–3519.

105. Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild

M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA,

Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander

ES. Identification of a gene causing human cytochrome coxidase

deficiency by integrative genomics. Proc Natl Acad Sci USA.

2003;100(2):605–610.

106. Ghaddhab C, Morin C, Brunel-Guitton C, Mitchell GA, Van Vliet

G, Huot C. Premature ovarian failure in French Canadian Leigh

syndrome. J Pediatr. 2017;184:227–229.e1.

107. Debray FG, Morin C, Janvier A, Villeneuve J, Maranda B,

Laframboise R, Lacroix J, Decarie JC, Robitaille Y, Lambert M,

Robinson BH, Mitchell GA. LRPPRC mutations cause a phe-

notypically distinct form of Leigh syndrome with cytochrome c

oxidase deficiency. J Med Genet. 2011;48(3):183–189.

108. Amunts A, Brown A, Toots J, Scheres SH, Ramakrishnan V. The

structure of the human mitochondrial ribosome. Science. 2015;

348(6230):95–98.

109. Emdadul Haque M, Grasso D, Miller C, Spremulli LL, Saada A.

The effect of mutated mitochondrial ribosomal proteins S16 and

S22 on the assembly of the small and large ribosomal subunits in

human mitochondria. Mitochondrion. 2008;8(3):254–261.

110. Chen A, Tiosano D, Guran T, Baris HN, Bayram Y, Mory A,

Shapiro-Kulnane L, Hodges CA, Akdemir ZC, Turan S, Jhangiani

SN, van den Akker F, Hoppel CL, Salz HK, Lupski JR, Buchner

DA. Mutations in the mitochondrial ribosomal protein MRPS22

lead to primary ovarian insufficiency. Hum Mol Genet. 2018;

27(11):1913–1926.

111. Jolly A, Bayram Y, Turan S, Aycan Z, Tos T, Abali ZY,

Hacihamdioglu B, Coban Akdemir ZH, Hijazi H, Bas S, Atay Z,

Guran T, Abali S, Bas F, Darendeliler F, Colombo R, Barakat TS,

Rinne T, White JJ, Yesil G, Gezdirici A, Gulec EY, Karaca E,

Pehlivan D, Jhangiani SN, Muzny DM, Poyrazoglu S, Bereket A,

Gibbs RA, Posey JE, Lupski JR. Exome sequencing of a primary

ovarian insufficiency cohort reveals common molecular etiologies

for a spectrum of disease. J Clin Endocrinol Metab. 2019;104(8):

3049–3067.

112. Saada A, Shaag A, Arnon S, Dolfin T, Miller C, Fuchs-Telem D,

Lombes A, Elpeleg O. Antenatal mitochondrial disease caused by

mitochondrial ribosomal protein (MRPS22) mutation. JMed

Genet. 2007;44(12):784–786.

113. Smits P, Saada A, Wortmann SB, Heister AJ, Brink M, Pfundt R,

Miller C, Haas D, Hantschmann R, Rodenburg RJ, Smeitink

JAM, van den Heuvel LP. Mutation in mitochondrial ribosomal

protein MRPS22 leads to Cornelia de Lange-like phenotype, brain

abnormalities and hypertrophic cardiomyopathy. Eur J Hum

Genet. 2011;19(4):394–399.

114. Baertling F, Haack TB, Rodenburg RJ, Schaper J, Seibt A, Strom

TM, Meitinger T, Mayatepek E, Hadzik B, Selcan G, Prokisch H,

Distelmaier F. MRPS22 mutation causes fatal neonatal lactic

acidosis with brain and heart abnormalities. Neurogenetics. 2015;

16(3):237–240.

115. KılıçM,O

˘guz K-K, KılıçE,Y¨uksel D, Demirci H, Sa ˘gıro ˘glu MS

¸,

Y¨ucel-Yılmaz D, ¨

Ozg ¨ul RK. A patient with mitochondrial dis-

order due to a novel mutation in MRPS22. Metab Brain Dis.

2017;32(5):1389–1393.

116. Hochberg I, Demain LA, Urquhart JE, Amberger A, Deutschmann

AJ, Demetz S, Thompson K, O’Sullivan J, Belyantseva IA, Barzik

M, Williams SG, Bhaskar SS, Jenkinson EM, AlSheqaih N,

Blumenfeld Z, Yalonetsky S, Oerum S, Rossmanith W, Yue WW,

Zschocke J, Taylor RW, Friedman TB, Munro KJ, O’Keefe RT,

Newman WG. A homozygous variant in mitochondrial RNase P

subunit PRORP is associated with Perrault syndrome charac-

terized by hearing loss and primary ovarian insufficiency. bio-

Rxiv. 2017:168252.

117. Menezes MJ, Guo Y, Zhang J, Riley LG, Cooper ST, Thorburn

DR, Li J, Dong D, Li Z, Glessner J, Davis RL, Sue CM, Alexander

SI, Arbuckle S, Kirwan P, Keating BJ, Xu X, Hakonarson H,

Christodoulou J. Mutation in mitochondrial ribosomal protein S7

(MRPS7) causes congenital sensorineural deafness, progressive

hepatic and renal failure and lactic acidemia. Hum Mol Genet.

2015;24(8):2297–2307.

118. Demain LA, Antunes D, O’Sullivan J, Bhaskhar SS, O’Keefe RT,

Newman WG. A known pathogenic variant in the essential mi-

tochondrial translation gene RMND1 causes a Perrault-like

syndrome with renal defects. Clin Genet. 2018;94(2):276–277.

119. Ng YS, Alston CL, Diodato D, Morris AA, Ulrick N, Kmoch S,

Houˇstˇek J, Martinelli D, Haghighi A, Atiq M, Gamero MA,

Garcia-Martinez E, Kratochv´

ılov´a H, Santra S, Brown RM,

Brown GK, Ragge N, Monavari A, Pysden K, Ravn K, Casey JP,

Khan A, Chakrapani A, Vassallo G, Simons C, McKeever K,

O’Sullivan S, Childs AM, Østergaard E, Vanderver A, Goldstein

A, Vogt J, Taylor RW, McFarland R. The clinical, biochemical

and genetic features associated with RMND1-related mito-

chondrial disease. J Med Genet. 2016;53(11):768–775.

120. Janer A, Antonicka H, Lalonde E, Nishimura T, Sasarman F,

Brown GK, Brown RM, Majewski J, Shoubridge EA. An RMND1

mutation causes encephalopathy associated with multiple oxi-

dative phosphorylation complex deficiencies and a mitochondrial

translation defect. Am J Hum Genet. 2012;91(4):737–743.

121. Garcia-Diaz B, Barros MH, Sanna-Cherchi S, Emmanuele V,

Akman HO, Ferreiro-Barros CC, Horvath R, Tadesse S, El

Gharaby N, DiMauro S, De Vivo DC, Shokr A, Hirano M,

Quinzii CM. Infantile encephaloneuromyopathy and defective

mitochondrial translation are due to a homozygous RMND1

mutation. Am J Hum Genet. 2012;91(4):729–736.

122. Posey JE, O’Donnell-Luria AH, Chong JX, Harel T, Jhangiani

SN, Coban Akdemir ZH, Buyske S, Pehlivan D, Carvalho CMB,

Baxter S, Sobreira N, Liu P, Wu N, Rosenfeld JA, Kumar S,

Avramopoulos D, White JJ, Doheny KF, Witmer PD, Boehm C,

doi: 10.1210/en.2019-00441 https://academic.oup.com/endo 2365

Downloaded from https://academic.oup.com/endo/article/160/10/2353/5544515 by guest on 12 June 2023

Sutton VR, Muzny DM, Boerwinkle E, G ¨unel M, Nickerson DA,

Mane S, MacArthur DG, Gibbs RA, Hamosh A, Lifton RP,

Matise TC, Rehm HL, Gerstein M, Bamshad MJ, Valle D, Lupski

JR; Centers for Mendelian Genomics. Insights into genetics,

human biology and disease gleaned from family based genomic

studies. Genet Med. 2019;21(4):798–812.

123. Venkatesh S, Kumar M, Sharma A, Kriplani A, Ammini AC,

Talwar P, Agarwal A, Dada R. Oxidative stress and ATPase6

mutation is associated with primary ovarian insufficiency. Arch

Gynecol Obstet. 2010;282(3):313–318.

124. Zhen X, Wu B, Wang J, Lu C, Gao H, Qiao J. Increased incidence

of mitochondrial cytochrome c oxidase 1 gene mutations in pa-

tients with primary ovarian insufficiency. PLoS One. 2015;10(7):

e0132610.

125. Palanichamy MG, Zhang Y-P. Are ATPase6 polymorphisms

associated with primary ovarian insufficiency? Arch Gynecol

Obstet. 2011;283(3):671–672.

126. Kumar M, Pathak D, Venkatesh S, Kriplani A, Ammini AC, Dada

R. Chromosomal abnormalities & oxidative stress in women with

premature ovarian failure (POF). Indian J Med Res. 2012;135(1):

92–97.

127. Kumar M, Pathak D, Kriplani A, Ammini AC, Talwar P, Dada R.

Nucleotide variations in mitochondrial DNA and supra-

physiological ROS levels in cytogenetically normal cases of pre-

mature ovarian insufficiency. Arch Gynecol Obstet. 2010;282(6):

695–705.

128. Ding Y, Xia BH, Zhuo GC, Zhang CJ, Leng JH. Premature

ovarian insufficiency may be associated with the mutations in

mitochondrial tRNA genes. Endocr J. 2019;66(1):81–88.

129. Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E,

Yavorska T, Naranian T, Chi M, Wang Y, Bentov Y, Alexis J,

Meriano J, Sung H-K, Gasser DL, Moley KH, Hekimi S, Casper

RF, Jurisicova A. Coenzyme Q10 restores oocyte mitochondrial

function and fertility during reproductive aging. Aging Cell. 2015;

14(5):887–895.

130. Boczonadi V, Smith PM, Pyle A, Gomez-Duran A, Schara U,

Tulinius M, Chinnery PF, Horvath R. Altered 2-thiouridylation

impairs mitochondrial translation in reversible infantile re-

spiratory chain deficiency. Hum Mol Genet. 2013;22(22):

4602–4615.

131. Wang G, Shimada E, Zhang J, Hong JS, Smith GM, Teitell MA,

Koehler CM. Correcting human mitochondrial mutations with

targeted RNA import. Proc Natl Acad Sci USA. 2012;109(13):

4840–4845.

132. Perli E, Giordano C, Pisano A, Montanari A, Campese AF, Reyes

A, Ghezzi D, Nasca A, Tuppen HA, Orlandi M, Di Micco P, Poser

E, Taylor RW, Colotti G, Francisci S, Morea V, Frontali L,

Zeviani M, d’Amati G. The isolated carboxy-terminal domain of

human mitochondrial leucyl-tRNA synthetase rescues the path-

ological phenotype of mitochondrial tRNA mutations in human

cells. EMBO Mol Med. 2014;6(2):169–182.

133. Hornig-Do HT, Montanari A, Rozanska A, Tuppen HA, Almalki

AA, Abg-Kamaludin DP, Frontali L, Francisci S, Lightowlers RN,

Chrzanowska-Lightowlers ZM. Human mitochondrial leucyl

tRNA synthetase can suppress non cognate pathogenic mt-tRNA

mutations. EMBO Mol Med. 2014;6(2):183–193.

134. Zhao X, Han J, Zhu L, Xiao Y, Wang C, Hong F, Jiang P, Guan

M-X. Overexpression of human mitochondrial alanyl-tRNA

synthetase suppresses biochemical defects of the mt-tRNA

Ala

mutation in cybrids. Int J Biol Sci. 2018;14(11):1437–1444.

135. Gadaleta MN, Petruzzella V, Daddabbo L, Olivieri C, Fracasso F,

Loguercio Polosa P, Cantatore P. Mitochondrial DNA tran-

scription and translation in aged rat. Effect of acetyl-L-carnitine.

Ann N Y Acad Sci. 1994;717(1):150–160.

136. Liang LF, Qi ST, Xian YX, Huang L, Sun XF, Wang WH.

Protective effect of antioxidants on the pre-maturation aging of

mouse oocytes. Sci Rep. 2017;7(1):1434.

137. Zare Z, Masteri Farahani R, Salehi M, Piryaei A, Ghaffari Novin

M, Fadaei Fathabadi F, Mohammadi M, Dehghani-

Mohammadabadi M. Effect of L-carnitine supplementation on

maturation and early embryo development of immature mouse

oocytes selected by brilliant cresyle blue staining. J Assist Reprod

Genet. 2015;32(4):635–643.

138. Yamada T, Imai H, Yamada M. Beneficial effects of acetyl-L-

carnitine treatment during IVM on post-fertilization development

of bovine oocytes in vitro. Reprod Fertil Dev. 2006;18(2):280.

139. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ,

Nickerson DA, Shendure J. Exome sequencing as a tool for

Mendelian disease gene discovery. Nat Rev Genet. 2011;12(11):

745–755.

140. Committee on Adolescent Health Care. Committee opinion no.

605: primary ovarian insufficiency in adolescents and young

women. Obstet Gynecol. 2014;124(1):193–197.

141. Stark Z, Schofield D, Alam K, Wilson W, Mupfeki N, Macciocca

I, Shrestha R, White SM, Gaff C. Prospective comparison of the

cost-effectiveness of clinical whole-exome sequencing with that of

usual care overwhelmingly supports early use and reimbursement.

Genet Med. 2017;19(8):867–874.

142. Monroe GR, Frederix GW, Savelberg SMC, de Vries TI, Duran

KJ, van der Smagt JJ, Terhal PA, van Hasselt PM, Kroes HY,

Verhoeven-Duif NM, Nijman IJ, Carbo EC, van Gassen KL,

Knoers NV, H ¨ovels AM, van Haelst MM, Visser G, van Haaften

G. Effectiveness of whole-exome sequencing and costs of the

traditional diagnostic trajectory in children with intellectual

disability. Genet Med. 2016;18(9):949–956.

143. Tan TY, Dillon OJ, Stark Z, Schofield D, Alam K, Shrestha R,

Chong B, Phelan D, Brett GR, Creed E, Jarmolowicz A, Yap P,

Walsh M, Downie L, Amor DJ, Savarirayan R, McGillivray G,

Yeung A, Peters H, Robertson SJ, Robinson AJ, Macciocca I,

Sadedin S, Bell K, Oshlack A, Georgeson P, Thorne N, Gaff C,

White SM. Diagnostic impact and cost-effectiveness of whole-

exome sequencing for ambulant children with suspected mono-

genic conditions. JAMA Pediatr. 2017;171(9):855–862.

144. Stark Z, Tan TY, Chong B, Brett GR, Yap P, Walsh M, Yeung A,

Peters H, Mordaunt D, Cowie S, Amor DJ, Savarirayan R,

McGillivray G, Downie L, Ekert PG, Theda C, James PA, Yaplito-

Lee J, Ryan MM, Leventer RJ, Creed E, Macciocca I, Bell KM,

Oshlack A, Sadedin S, Georgeson P, Anderson C, Thorne N, Gaff

C, White SM; Melbourne Genomics Health Alliance. A pro-

spective evaluation of whole-exome sequencing as a first-tier

molecular test in infants with suspected monogenic disorders.

Genet Med. 2016;18(11):1090–1096.

145. Vissers LE, van Nimwegen KJ, Schieving JH, Kamsteeg EJ,

Kleefstra T, Yntema HG, Pfundt R, van der Wilt GJ, Krabbenborg

L, Brunner HG, van der Burg S, Grutters J, Veltman JA,

Willemsen MA. A clinical utility study of exome sequencing

versus conventional genetic testing in pediatric neurology. Genet

Med. 2017;19(9):1055–1063.

146. Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N,

Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G,

Yuen RK, Szego MJ, Hayeems RZ, Shaul RZ, Brudno M,

GirdeaM,FreyB,AlipanahiB,AhmedS,Babul-HirjiR,Porras

RB, Carter MT, Chad L, Chaudhry A, Chitayat D, Doust SJ,

Cytrynbaum C, Dupuis L, Ejaz R, Fishman L, Guerin A,

Hashemi B, Helal M, Hewson S, Inbar-Feigenberg M, Kannu P,

Karp N, Kim R, Kronick J, Liston E, MacDonald H, Mercimek-

Mahmutoglu S, Mendoza-Londono R, Nasr E, Nimmo G,

Parkinson N, Quercia N, Raiman J, Roifman M, Schulze A,

Shugar A, Shuman C, Sinajon P, Siriwardena K, Weksberg R,

Yoon G, Carew C, Erickson R, Leach RA, Klein R, Ray PN,

Meyn MS, Scherer SW, Cohn RD, Marshall CR. Whole-

genome sequencing expands diagnostic utility and improves

clinical management in paediatric medicine. NPJ Genom Med.

2016;1(1):15012.

2366 Tiosano et al Mitochondrial Dysfunction in POI Endocrinology, October 2019, 160(10):2353–2366

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MA demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis

Article

Full-text available

Jun 2024

Background Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m⁶A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion H-Exs secreted circBRCA1 regulated by m⁶A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI. Graphical Abstract

Transcriptomic profile of premature ovarian insufficiency with RNA-sequencing

Article

Full-text available

Apr 2024

Introduction This study aimed to explore the transcriptomic profile of premature ovarian insufficiency (POI) by investigating alterations in gene expression. Methods A total of sixty-one women, comprising 31 individuals with POI in the POI group and 30 healthy women in the control group (HC group), aged between 24 and 40 years, were recruited for this study. The transcriptomic profiles of peripheral blood samples from all study subjects were analyzed using RNA-sequencing. Results The results revealed 39 differentially expressed genes in individuals with POI compared to healthy controls, with 10 upregulated and 29 downregulated genes. Correlation analysis highlighted the relationship between the expression of SLC25A39, CNIH3, and PDZK1IP1 and hormone levels. Additionally, an effective classification model was developed using SLC25A39, CNIH3, PDZK1IP1, SHISA4, and LOC389834. Functional enrichment analysis demonstrated the involvement of these differentially expressed genes in the “haptoglobin-hemoglobin complex,” while KEGG pathway analysis indicated their participation in the “Proteoglycans in cancer” pathway. Conclusion The identified genes could play a crucial role in characterizing the genetic foundation of POI, potentially serving as valuable biomarkers for enhancing disease classification accuracy.

Polyamines in Ovarian Aging and Disease

Article

Full-text available

Oct 2023
INT J MOL SCI

Ovarian aging and disease-related decline in fertility are challenging medical and economic issues with an increasing prevalence. Polyamines are a class of polycationic alkylamines widely distributed in mammals. They are small molecules essential for cell growth and development. Polyamines alleviate ovarian aging through various biological processes, including reproductive hormone synthesis, cell metabolism, programmed cell death, etc. However, an abnormal increase in polyamine levels can lead to ovarian damage and promote the development of ovarian disease. Therefore, polyamines have long been considered potential therapeutic targets for aging and disease, but their regulatory roles in the ovary deserve further investigation. This review discusses the mechanisms by which polyamines ameliorate human ovarian aging and disease through different biological processes, such as autophagy and oxidative stress, to develop safe and effective polyamine targeted therapy strategies for ovarian aging and the diseases.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism

Article

Full-text available

Jun 2024

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional.

METTL3 deficiency leads to ovarian insufficiency due to IL-1β overexpression in theca cells

Article

May 2024
FREE RADICAL BIO MED

Therapeutic Targets and Drug Leads for Reproductive Health

Chapter

Mar 2024

Reproductive health implies the total well-being of an individual in all aspects of reproduction, including physical, behavioral, emotional, and social well-being. Maintaining a functional reproductive health status is critical for ensuring community and family health. Reproductive disorders present a global health concern that considerably impacts human health and are more challenging to diagnose and treat, increasing the likelihood of comorbidity. Owing to the involvement of a multitude of factors in the development and pathophysiology of reproductive diseases, the identification of critical therapeutic targets becomes challenging. Factors influencing ovarian function and endometrial receptivity represent ideal treatment targets due to their importance in influencing fertility and successful pregnancy outcomes. Components of the immune system and inflammatory pathways are central to various reproductive events, which can be therapeutically manipulated for the management of reproductive pathologies in which inflammatory dysregulation plays a central role. Additionally, targeting the reproductive tract microbiota and pathogenic microbes involved in reproductive tract infections provides a promising approach to restoring reproductive health. Treatment of reproductive disorders mainly includes drugs for treating menstrual disorders, drugs for fertility treatments, and those for treating reproductive infections. Herbal medicines offer a holistic and safe approach to the management of reproductive disorders, and currently, a number of active compounds derived from natural sources have demonstrated the potential to develop into successful drug candidates. The chapter summarizes data on the different therapeutic targets in reproductive disorders with the description of potential drug leads that have proven promising in the management of reproductive pathologies.

Genetic Testing in Premature Ovarian Failure

Chapter

Mar 2024

Premature ovarian failure is defined as the lack of ovarian hormones or ovarian follicle reserve. This results in aberrant ovarian activity, which causes early oocyte depletion and the start of menopause. Amenorrhea, a review of the family history going back at least three generations, a pelvic sonogram, and a serum FSH level > 40 mIU/ml are all used to diagnose POF illness. The 2016 guidelines from the European Society of Human Reproduction and Embryology (ESHRE) recommended that amenorrhea be monitored for at least 4 months, increased FSH levels be tested for two consecutive months, and then karyotyping be used for genetic testing. 20–25% of the cases are believed to be genetic. A few genes have been discovered to affect the risk of POF, but 50–90% of the cases remain idiopathic. Since normal ovarian function is a complex process, many genes have yet to be discovered with a role in causing the disease. In this chapter, we have focused on genetic testing in POF cases. Different diagnostic methods, such as karyotyping, candidate gene sequencing, genome-wide association studies, whole genome/exome sequencing, array comparative genomic hybridization, and microarray, have been discussed in this chapter.

M6A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis

Preprint

Full-text available

Jan 2024

Background: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n=50) and patients with POI (n=50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m⁶A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion: H-Exs secreted circBRCA1 regulated by m⁶A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.

New insights on mitochondrial heteroplasmy observed in ovarian diseases

Article

Dec 2023

Transmission ratio distortion detection by neutral genetic markers in the Pura Raza Española horse breed

Article

Oct 2023
ANIMAL

Germline selection shapes human mitochondrial DNA diversity

Article

Full-text available

May 2019

Heteroplasmy incidence in mitochondrial DNA In humans, mitochondrial DNA (mtDNA) is predominantly maternally inherited. mtDNA is under selection to prevent heteroplasmy—the transmission of multiple genetic variants into the next generation. Wei et al. explored human mtDNA sequences to determine mtDNA genome structure, selection, and transmission. Whole-genome sequencing revealed that about 45% of individuals carry heteroplasmic mtDNA sequences at levels greater than 1% of their total mtDNA. Furthermore, studies of more than 1500 mother-offspring pairs indicated that the female line selected which mtDNA variants were passed on to children. This effect was influenced by the mother's nuclear genetic background. Thus, mtDNA is under selection at specific loci in the human germ line. Science , this issue p. eaau6520

Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum

Article

Full-text available

Feb 2019

Variants in the mitochondrial alanyl-tRNA synthetase 2 gene AARS2 (OMIM 612035) are associated with infantile mitochondrial cardiomyopathy or later-onset leukoencephalopathy with premature ovarian insufficiency. Here, we report two newborn siblings who died soon after birth with primary pulmonary hypoplasia without evidence of cardiomyopathy. Whole-exome sequencing detected the same compound heterozygous AARS2 variants in both siblings (c.1774C>T, p.Arg592Trp and c.647dup, p.Cys218Leufs*6) that have previously been associated with infantile mitochondrial cardiomyopathy. Segregation analysis in the family confirmed carrier status of the parents and an unaffected sibling. To our knowledge, this is the first report of primary pulmonary hypoplasia in the absence of cardiomyopathy associated with recessive AARS2 variants and further defines the phenotypic spectrum associated with this gene.

When a common biological role does not imply common disease outcomes: Disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases

Article

Full-text available

Jan 2019

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are essential components of the mitochondrial translation machinery. The correlation of mitochondrial disorders with mutations in these enzymes has raised the interest of the scientific community over the past several years. Most surprising has been the wide-ranging presentation of clinical manifestations in patients with mt-aaRS mutations, despite the enzymes’ common biochemical role. Even among cases where a common physiological system is affected, phenotypes, severity, and age of onset varies depending on which mt-aaRS is mutated. Here we review work done thus far and propose a categorization of diseases based on tissue specificity that highlights emerging patterns. We further discuss multiple in vitro and in cellulo efforts to characterize the behavior of wildtype and mutant mt-aaRSs that have shaped hypotheses about the molecular causes of these pathologies. Much remains to do in order to complete our understanding of these proteins. We expect that futher work is likely to result in the discovery of new roles for the mt-aaRSs in addition to their fundamental function in mitochondrial translation, informing the development of treatment strategies and diagnoses.

Recent Advances in Mitochondrial Aminoacyl-tRNA Synthetases and Disease

Article

Aug 2017

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

Article

May 2019

Context Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75-90% of individuals with hypergonadotropic hypogonadism (HH) presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and non-syndromic single gene disorders suggesting POI represents a complex trait. Objective To characterize the contribution of known disease genes to POI and identify novel molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and 5 families with predicted deleterious variants in novel disease genes (IGSF10, MND1, MRPS22, and SOHLH1). Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity (AOH) consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions ES analysis of a POI cohort further characterized locus heterogeneity, re-affirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multi-locus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

Insights into genetics, human biology and disease gleaned from family based genomic studies

Article

Jan 2019
GENET MED

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel “disease gene” discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

Mitochondrial proteins: from biogenesis to functional networks

Article

Jan 2019

Mitochondria are essential for the viability of eukaryotic cells as they perform crucial functions in bioenergetics, metabolism and signalling and have been associated with numerous diseases. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. In this Review, we discuss the emerging role of the mitochondrial protein import machinery as a key organizer of these mitochondrial protein networks. The preprotein translocases that reside on the mitochondrial membranes not only function during organelle biogenesis to deliver newly synthesized proteins to their final mitochondrial destination but also cooperate with numerous other mitochondrial protein complexes that perform a wide range of functions. Moreover, these protein networks form membrane contact sites, for example, with the endoplasmic reticulum, that are key for integration of mitochondria with cellular function, and defects in protein import can lead to diseases.

Genetics and Genomics of Primary Ovarian Insufficiency

Chapter

Jan 2019

Article

Nov 2018
NAT REV NEUROL

The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers–Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.

Premature ovarian insufficiency may be associated with the mutations in mitochondrial tRNA genes

Article

Nov 2018

Premature ovarian insufficiency (POI) is a common endocrine disorder featured by the triad constituting of amenorrhea for at least four months, to date, the molecular pathogenesis of POI is largely undetermined. Despite several investigations have reported an increase in reactive oxygen species (ROS) content in idiopathic POI, the role of mitochondrial DNA (mtDNA) mutations/variants in the progression of POI has not been widely investigated. The current study aimed to explore the association between mt-tRNA mutations/variants and POI; we first used the PCR-Sanger sequencing to detect the mutations/variants in mt-tRNA genes from 50 POI patients and 30 healthy subjects. In addition, we evaluated the mitochondrial functions by using trans-mitochondrial cybrid cells containing these potential pathogenic mt-tRNA mutations. Consequently, five mutations: tRNALeu(UUR) C3303T, tRNAMet A4435G, tRNAGln T4363C, tRNACys G5821A and tRNAThr A15951G were identified. Notably, these mutations occurred at the extremely conserved nucleotides of the corresponding mt-tRNAs and may result the failure in mt-tRNA metabolism and subsequently lead to the impairment in mitochondrial protein synthesis. Furthermore, biochemical and molecular analyses of the cybrid cells containing these mutations showed a significantly lower level of ATP production when compared with the controls, whereas the ROS levels were much higher in POI patients carrying these mt-tRNA mutations, strongly indicated that these mt-tRNA mutations may cause the mitochondrial dysfunction, and play active roles in the progression and pathogensis of POI. Together, this study shaded additional light on the molecular mechanism of POI that was manifestated by mt-tRNA mutations.

Mitochondrial Dysfunction in Primary Ovarian Insufficiency

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