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Clover leaf-shaped secondary tRNA structure. (A) clover leaf-shaped structure includes the acceptor stem, D-loop, D-stem, anticodon (AC)-stem, AC-loop, T-loop, T-stem and variable (V) region. (B–L) tRNAs mutations associated with cardiac disease and EH.
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Essential hypertension (EH) is one of the most common cardiovascular diseases worldwide, entailing a high level of morbidity. EH is a multifactorial disease influenced by both genetic and environmental factors, including mitochondrial DNA (mtDNA) genotype. Previous studies identified mtDNA mutations that are associated with maternally inherited hyp...
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Mitochondrial dynamics, such as fusion and fission, play a critical role in maintaining cellular metabolic homeostasis. The molecular mechanisms underlying these processes include fusion proteins (Mitofusin 1 [MFN1], Mitofusin 2 [MFN2], and optic atrophy 1 [OPA1]) and fission mediators (mitochondrial fission 1 [FIS1] and dynamin-related protein 1 [...
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... Besides these core PCGs, the two mitogenomes of Apiotrichum species varied in rRNA and tRNA sizes and base composition. The size and base composition variations of tRNA have been reported to affect the protein synthesis efficiency (Lin et al. 2021;Liu and Chen 2020), and the effect of tRNA variations on protein synthesis of Apiotrichum species needs to be further verified. In addition, we found some non-conserved PCGs in the two Apiotrichum mitogenomes, which encoded proteins with unknown functions. ...
Apiotrichum is a diverse anamorphic basidiomycetous yeast genus, and its mitogenome characterization has not been revealed. In this study, we assembled two Apiotrichum mitogenomes and compared them with mitogenomes from Agaricomycotina , Pucciniomycotina and Ustilaginomycotina . The mitogenomes of Apiotrichum gracile and A. gamsii comprised circular DNA molecules, with sizes of 34,648 bp and 38,096 bp, respectively. Intronic regions were found contributed the most to the size expansion of A. gamsii mitogenome. Comparative mitogenomic analysis revealed that 6.85–38.89% of nucleotides varied between tRNAs shared by the two Apiotrichum mitogenomes. The GC content of all core PCGs in A. gamsii was lower than that of A. gracile , with an average low value of 4.97%. The rps3 gene differentiated the most among Agaricomycotina, Pucciniomycotina and Ustilaginomycotina species, while nad4L gene was the most conserved in evolution. The Ka/Ks values for cob and rps3 genes were > 1, indicating the two genes may be subjected to positive selection in Agaricomycotina, Pucciniomycotina and Ustilaginomycotina . Frequent intron loss/gain events and potential intron transfer events have been detected in evolution of Agaricomycotina, Pucciniomycotina and Ustilaginomycotina . We further detected large-scale gene rearrangements between the 19 mitogenomes from Agaricomycotina, Pucciniomycotina and Ustilaginomycotina , and fifteen of the 17 mitochondrial genes shared by Apiotrichum varied in gene arrangements. Phylogenetic analyses based on maximum likelihood and Bayesian inference methods using a combined mitochondrial gene dataset revealed different taxonomic assignment of two Apiotrichum species, wherein A. gamsii had a more closely relationship with Trichosporon asahii . This study served as the first report on mitogenomes from the genus Apiotrichum , which promotes the understanding of evolution, genomics, and phylogeny of Apiotrichum .
... [16][17][18][19][20] The deficiency of mtDNA-encoded proteins further leads to mitochondrial dysfunction along with ATP production decrease and reactive oxygen species (ROS) level increase. [21][22][23][24] In human tRNA Phe , the G583A mutation (G007A in rat) resulted in significant losses in aminoacylation efficiency by hmt-PheRS, which could impair the translation of mtDNA-encoded proteins. 25 The G007A mutation results in tRNA metabolism impairment and further leads to the decrease of mitochondrial proteins and ATP production in rats. ...
Animal model harboring pathogenic mitochondrial DNA (mtDNA) mutations is important to understand the biological links between mtDNA variation and mitochondrial diseases. DdCBE, a DddA-derived cytosine base editor, has been utilized in zebrafish, mice, and rats for tC sequence-context targeting and human mitochondrial disease modeling. However, human pathogenic mtDNA mutations other than the tC context cannot be manipulated. Here, we screened the combination of different DdCBE pairs at pathogenic mtDNA mutation sites with nC (n for a, g or c) context and identified that the L1333C + R1333N pair could mediate C∙G-to-T∙A conversion effectively at aC sites in rat C6 cells. The editing efficiency at disease-associated mtDNA mutation sites within aC context was further confirmed to be up to 67.89% in vivo. Also, the installed disease-associated mtDNA mutations were germline-transmittable. Moreover, the edited rats showed impaired cardiac function and mitochondrial function, resembling human mitochondrial disease symptoms. In summary, for the first time, we expanded the DdCBE targeting scope to aC motif and installed the pathogenic mutation in rats to model human mitochondrial diseases.
... Determining the effect of mitochondrial DNA mutations on energy production and mitochondrial dysfunction would improve the understanding of heart development. The nucleotide changes in the mtDNA were reported to lead to important defects in the concentration of several respiratory enzymes and transfer RNAs (tRNAs) directly synthesized in the mitochondria (Mayr et al., 2015;Liu and Chen, 2020). Moreover, some inherited mtDNA polymorphisms that are not directly related to any form of pathology have been shown to affect mitochondrial function (Bray and Ballinger, 2017). ...
... We then established that the generation of ATP was reduced in cells harboring mtDNA point mutation variants in comparison to the control, suggesting that variations impair the function of the respiration chain and inhibit mitochondrial ATP synthesis. Recent studies have shown that the mt-tRNA point mutations and missense mutations resulted in a significant reduction of the activity of mitochondrial complexes I, III, IV, and V, leading to lower levels of ATP production (Ganetzky et al., 2019;Liu and Chen, 2020). Cells from patients with TOF who carried the 4316AG (in T-loop tRNA ILe ), 5543T>C (in the anticodon loop of tRNA Trp ), 5727G>T (in ACC-stem of tRNA Asn ), 8878C>G, 8874C>G (Arg118Gly, Gly116Gly in ATPase6) mutations had 58.83 % lower ATP generation level than control cells. ...
Most studies aiming at unraveling the molecular events associated with cardiac congenital heart disease (CHD) have focused on the effect of mutations occurring in the nuclear genome. In recent years, a significant role has been attributed to mitochondria for correct heart development and maturation of cardiomyocytes. Moreover, numerous heart defects have been associated with nucleotide variations occurring in the mitochondrial genome, affecting mitochondrial functions and cardiac energy metabolism, including genes encoding for subunits of respiratory chain complexes. Therefore, mutations in the mitochondrial genome may be a major cause of heart disease, including CHD, and their identification and characterization can shed light on pathological mechanisms occurring during heart development. Here, we have analyzed mitochondrial genetic variants in previously reported mutational genome hotspots and the flanking regions of mt-ND1, mt-ND2, mt-COXI, mt-COXII, mt-ATPase8, mt-ATPase6, mt-COXIII, and mt-tRNAs (Ile, Gln, Met, Trp, Ala, Asn, Cys, Tyr, Ser, Asp, and Lys) encoding genes by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) in 200 patients with CHD, undergoing cardiac surgery. A total of 23 mitochondrial variations (5 missense mutations, 8 synonymous variations, and 10 nucleotide changes in tRNA encoding genes) were identified and included 16 novel variants. Additionally, we showed that intracellular ATP was significantly reduced (P=0.002) in CHD patients compared with healthy controls, suggesting that the mutations have an impact on mitochondrial energy production. Functional and structural alterations caused by the mitochondrial nucleotide variations in the gene products were studied in-silico and predicted to convey a predisposing risk factor for CHD. Further studies are necessary to better understand the mechanisms by which the alterations identified in the present study contribute to the development of CHD in patients.
... Determining the effect of mitochondrial DNA mutations on energy production and mitochondrial dysfunction would improve the understanding of heart development. The nucleotide changes in the mtDNA were reported to lead to important defects in the concentration of several respiratory enzymes and transfer RNAs (tRNAs) directly synthesized in the mitochondria (Mayr et al., 2015;Liu and Chen, 2020). Moreover, some inherited mtDNA polymorphisms that are not directly related to any form of pathology have been shown to affect mitochondrial function (Bray and Ballinger, 2017). ...
... We then established that the generation of ATP was reduced in cells harboring mtDNA point mutation variants in comparison to the control, suggesting that variations impair the function of the respiration chain and inhibit mitochondrial ATP synthesis. Recent studies have shown that the mt-tRNA point mutations and missense mutations resulted in a significant reduction of the activity of mitochondrial complexes I, III, IV, and V, leading to lower levels of ATP production (Ganetzky et al., 2019;Liu and Chen, 2020). Cells from patients with TOF who carried the 4316AG (in T-loop tRNA ILe ), 5543T>C (in the anticodon loop of tRNA Trp ), 5727G>T (in ACC-stem of tRNA Asn ), 8878C>G, 8874C>G (Arg118Gly, Gly116Gly in ATPase6) mutations had 58.83 % lower ATP generation level than control cells. ...
... Similarly, studies of mitochondrial variants associated with familial hypertension and coronary heart disease demonstrate an increased prevalence of variants in mitochondrial tRNA coding genes. Functional studies in this patient population report defects in tRNA structure leading to decreased energy production and subsequent ROS [120,121]. Further research into the utility of mtDNA sequencing for polygenetic and multifactorial cardiovascular disease may help guide identifying at-risk individuals and the development of therapeutics in this patient population. ...
... Due to the composition of the mtDNA, the majority of mtDNA pathogenic variants are in tRNA coding genes ( Figure 2). While heterogenous, overall, pathogenic variants in tRNA coding genes can impair transcriptional termination, post-transcriptional modifications, and the translation of proteins from the mtDNA [121,123]. The downstream effect being lowered mitochondrial fitness and respiration capacity. ...
Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.
... Previous studies identified mtDNA mutations that are associated with maternally inherited hypertension, including tRNA Ile m.4263A>G, m.4291T>C, m.4295A>G, tRNA Met m.4435A>G, tRNA Ala m.5655A>G, and tRNA Met / tRNA Gln m.4401A>G. (21,(32)(33)(34)(47)(48)(49) Majamaa-Voltti et al. (50) found that LVH was the most common cardiac abnormality in pedigrees with the 3243A>G mtDNA mutation. ...
Arterial hypertension remains a major modifiable risk factor for cardiovascular disease. Previous studies have noted a maternal effect on blood pressure (BP). Mutations in mitochondrial DNA (mtDNA) have become an additional target of investigations on the missing BP heritability. The major objective of the present work was to investigate mutations in the tRNA Leu(UUR) gene in 20 Pakistani patients with essential hypertension (EH) and compare the amplified sequences to the mitochondrial reference sequence. DNA was extracted from their saliva, and the mitochondrial tRNA Leu(UUR) gene was amplified using PCR with specified primers. The present study did not find mutations in the tRNA Leu(UUR) gene in Pakistani EH patients. Further studies are needed for confirmation.(International Journal of Biomedicine. 2022;12(3):444-449.). Abbreviations AQ-seq, accurate quantification by sequencing; BP, blood pressure; EH, essential hypertension; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; mtDNA, mitochondrial DNA; PCR, polymerase chain reaction; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxidative species; tRNA, transfer RNA.
... Some bases are part of two different genes; i. e., a base that serves as the end of one gene may also serve as the beginning of the next gene [18]; thus, even small changes in the mtDNA sequence due to ROS oxidation may result in changes in structurally important genes within the mtDNA genome. (4) Excessive production of ROS mediates mtDNA damage and mutations: mtDNA mutations alter tRNA structure, which affects protein synthesis and leads to defective OXPHOS, further increasing ROS production and exacerbating mtDNA mutations, forming a vicious cycle [19]. ...
According to the latest Global Burden of Disease Study, cardiovascular disease (CVD) is the leading cause of death, and ischemic heart disease and stroke are the cause of death in approximately half of CVD patients. In CVD, mitochondrial dysfunction following ischemia-reperfusion (I/R) injury results in heart failure. The proper functioning of oxidative phosphorylation (OXPHOS) and the mitochondrial life cycle in cardiac mitochondria are closely related to mitochondrial DNA (mtDNA). Following myocardial I/R injury, mitochondria activate multiple repair and clearance mechanisms to repair damaged mtDNA. When these repair mechanisms are insufficient to restore the structure and function of mtDNA, irreversible mtDNA damage occurs, leading to mtDNA mutations. Since mtDNA mutations aggravate OXPHOS dysfunction and affect mitophagy, mtDNA mutation accumulation leads to leakage of mtDNA and proteins outside the mitochondria, inducing an innate immune response, aggravating cardiovascular injury, and leading to the need for external interventions to stop or slow the disease course. On the other hand, mtDNA released into the circulation after cardiac injury can serve as a biomarker for CVD diagnosis and prognosis. This article reviews the pathogenic basis and related research findings of mtDNA oxidative damage and mtDNA leak-triggered innate immune response associated with I/R injury in CVD and summarizes therapeutic options that target mtDNA.
... On the other hand, aaRSs are also highly discriminating enzymes. Even within mitochondrial translation systems, there are multiple examples of single nucleotide substitutions in mt-tRNAs resulting in severe reductions in aminoacylation (Yarham et al. 2010;Liu and Chen 2020). In one described case of aaRS/tRNA incompatibility in Drosophila, a single amino acid polymorphism in the mitochondrial TyrRS negatively interacted with a nucleotide polymorphism in mt-tRNA-Tyr to produce a diseased phenotype of delayed development and reduced fecundity (Meiklejohn et al. 2013). ...
The number of tRNAs encoded in plant mitogenomes varies considerably, with some lineages exhibiting rapid reductions. Loss of these bacterial-like mitochondrial tRNAs necessitates the import of nuclear-encoded counterparts that share little sequence similarity, raising questions about the identity and trafficking of enzymes necessary for the maturation and function of these newly imported tRNAs. In particular, the aminoacyl tRNA synthetases (aaRSs) that charge tRNAs are usually divided into distinct classes that specialize on either organellar or cytosolic tRNAs. Here, we investigated the evolution of aaRS subcellular localization in five species from a plant lineage (Sileneae) that has experienced extensive and rapid mitochondrial tRNA loss. By analyzing full-length mRNA transcripts (PacBio Iso-Seq), we found predicted retargeting of many ancestrally cytosolic aaRSs to the mitochondrion as well as scenarios where enzyme localization does not appear to change despite functional tRNA replacement. In most cases of transit peptide acquisition, the cytosolic enzyme gained a coding extension prior to the loss of the cognate mitochondrial tRNAs - suggesting a transitional state where organellar and cytosolic aaRSs colocalize to mitochondria. The ongoing functional replacement of Sileneae mitochondrial tRNAs and subsequent evolution of tRNA-interacting enzymes present an opportunity to study the coevolutionary dynamics of plant cytonuclear genetics.
... 9 Numerous variants in the mitochondrial genome that are associated with maternally inherited essential hypertension have been described, and many of them affect genes encoding for tRNAs. 10 tRNAs are complex molecules that in the first instance enable protein biosynthesis by decoding the transcript and translating it into amino acids. Depending on the position of a genetic variation within tRNAs the efficiency of protein biosynthesis can be altered in numerous ways, with the potential to even result in altered amino acid sequence. ...
... Depending on the position of a genetic variation within tRNAs the efficiency of protein biosynthesis can be altered in numerous ways, with the potential to even result in altered amino acid sequence. 10 However, it has been increasingly recognized that tRNAs play roles beyond translation of mRNA into protein, and these include regulatory functions akin (yet mechanistically different) to those of noncoding RNA species such as microRNAs. 11 This explains why the effects of changes in tRNAs are not entirely predictable and to some extent occur at random, depending on changes in protein sequence and the regulatory functions of tRNAs. ...
... More strikingly, a metabolic phenotype characterized by an unfavorable lipid profile in these patients could well be related to changes in mitochondrial function and has been found in other patients with mitochondrial DNA mutations. 10 Patients are also characterized by hypomagnesaemia and while the mechanisms linking the genetic variants to magnesium homeostasis remain unclear the key role of Mg 2+ for mitochondrial function 12 and the pathophysiological links between Mg 2+ transporters and hypertension 13 are evident. ...
Hypertension is a complex clinical condition characterized by raised blood pressure. Apart from personal and environmental factors a genetic component of hypertension is well recognized. Heritability is estimated at 15%–40%.¹
In order to unravel the genetic factors that contribute to blood pressure regulation, and hence to hypertension, a multitude of strategies have been employed, driven by advances in understanding of our genetic make-up, technology, and our understanding of pathophysiology. Candidate gene approaches were among the first, in hindsight slightly naive, attempts to study the genetic component of hypertension. They were based on the assumption of strong effects of genetic variants on blood pressure, and the simplistic conception that genetic variation will be limited to or at least focused on major effectors such as vasoactive substances and their receptors. At a time when technology allowed first genome-wide approaches to undertake unbiased studies,2,3 there was considerable disappointment that “blood pressure genes” were not readily detected.⁴ We have since learned that effect sizes are much smaller than originally thought, that there are hundreds if not thousands of genetic variants associated with blood pressure regulation, and that they often affect genes that encode signaling and regulatory proteins, or are located in parts of the genome that do not directly relate to a specific gene or exon.
