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![A patient affected with Alpers-Huttenlocher (AHS) disease. (A,B) Head MRI scan (coronal plane, T2 weighed images). Bilateral focal hyperintensities are seen of the hemispheric cortex and thalami (A), of the white matter and cerebellar cortex (B). (C-F) Histological sections through cortical lesions of the same patient (HE stain; C, E, F, and GFAP; D). The pattern of the necrotizing lesions of the cortex is shown with microcavitation, vessel proliferation, neuronal loss (C), and the associated gliosis (D). Features of cell death: acute ischemic changes (arrow; E) and nuclear fragmentation (arrowhead; F) of two cortical neurons. Adapted from [132].](publication/358592874/figure/fig2/AS:1127442706116609@1645814696135/A-patient-affected-with-Alpers-Huttenlocher-AHS-disease-A-B-Head-MRI-scan-coronal.png)
A patient affected with Alpers-Huttenlocher (AHS) disease. (A,B) Head MRI scan (coronal plane, T2 weighed images). Bilateral focal hyperintensities are seen of the hemispheric cortex and thalami (A), of the white matter and cerebellar cortex (B). (C-F) Histological sections through cortical lesions of the same patient (HE stain; C, E, F, and GFAP; D). The pattern of the necrotizing lesions of the cortex is shown with microcavitation, vessel proliferation, neuronal loss (C), and the associated gliosis (D). Features of cell death: acute ischemic changes (arrow; E) and nuclear fragmentation (arrowhead; F) of two cortical neurons. Adapted from [132].
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Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation o...
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Background: Leigh syndrome is a rare, genetic, and severe mitochondrial disorder characterized by neuromuscular issues (ataxia, seizure, hypotonia, developmental delay, dystonia) and ocular abnormalities (nystagmus, atrophy, strabismus, ptosis). It is caused by pathogenic variants in either mitochondrial or nuclear DNA genes, with an estimated inci...
Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during n...
Key Clinical Message
In 1‐year‐old girl presenting with neurodegenerative mitochondrial disease (Leigh syndrome), mutation analysis was performed by whole exome sequencing. Pathogenic variants were then analyzed in parents and relatives by Sanger sequencing. We identified a point mutation c.G484A in NDUFS8 gene which was homozygous in patient and h...
Mitochondrial disorders are caused due to variants in genes located on the mitochondrial DNA or the nuclear DNA. Here, we report a case with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh overlap syndrome due to variant m.13513G>A in ND5. A 60-month-old female with a congenital, complex, multisystem phenotype...
Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes th...
Citations
... However, the mutation of ChrMT:6268C > T; Cox1: A122V is located in a topological domain of complex IV subunit 1 (encoded by the cox1 gene, Figure 4(b); ). Except for diferent volumes for amino acids "Ala" and "Val," the similar physiochemical features shared by these two amino acids (Figure 4) suggest that the A122V mutation alone is less likely to cause structural and/or functional changes (Figure 4(b)), which, however, requires further investigation, as the Cox1 structure gene mutation is extremely rare [35]. ...
... However, up to December 2023, none of the Cox1 variants have been reported, based on the database searching using . Not only Cox1 but also mutations that occurred in Cox structural genes, encoded by either mtDNA or nuclear DNA, are extremely rare [35]; a few identifed Cox defciency syndromes are due to mutations in the assembly factors [35]. However, diferent Cox1 defciency model systems, established using animals including Saccharomyces cerevisiae, Drosophila melanogaster, and Mus musculus, have demonstrated diverse phenotypes, including Leber hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia (AISA), ataxia, hypotonia, and epilepsy [37]. ...
... However, up to December 2023, none of the Cox1 variants have been reported, based on the database searching using . Not only Cox1 but also mutations that occurred in Cox structural genes, encoded by either mtDNA or nuclear DNA, are extremely rare [35]; a few identifed Cox defciency syndromes are due to mutations in the assembly factors [35]. However, diferent Cox1 defciency model systems, established using animals including Saccharomyces cerevisiae, Drosophila melanogaster, and Mus musculus, have demonstrated diverse phenotypes, including Leber hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia (AISA), ataxia, hypotonia, and epilepsy [37]. ...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM). Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue. Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein–Barr virus 24 years ago (mononucleosis). Before then, the patient was a healthy professional woman. A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase). CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP. Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria. These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes. Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient’s mitochondria and the development of her ME/CFS symptoms.
... Another layer of complexity originates from the fact that many phenotypic manifestations of PMDs are also common in the general population, such as migraine, hearing loss, and diabetes mellitus, thereby failing to raise suspicion of PMD [27]. ...
Mitochondrial disorders are a group of rare and heterogeneous genetic diseases characterized by dysfunctional mitochondria leading to deficient adenosine triphosphate synthesis and chronic energy deficit in patients. The majority of these patients exhibit a wide range of phenotypic manifestations targeting several organ systems, making their clinical diagnosis and management challenging. Bridging translational to clinical research is crucial for improving the early diagnosis and prognosis of these intractable mitochondrial disorders and for discovering novel therapeutic drug candidates and modalities. This review provides the current state of clinical testing in mitochondrial disorders, discusses the challenges and opportunities for converting basic discoveries into clinical settings, explores the most suited patient-centric approaches to harness the extraordinary heterogeneity among patients affected by the same primary mitochondrial disorder, and describes the current outlook of clinical trials.
... Immune-mediated inflammatory diseases of the nervous system were considered as a possibility; however, lumbar puncture done revealed a normal CSF picture and an autoimmune encephalitis panel (NMDA, VGKC, GABA A/B, MOG Ab) was also negative. Possibility of a mitochondrial cytopathy was thought of; however, extensive literature review failed to reveal the imaging feature [2] of a transverse pontine signal change in this clinical context, further perplexing us. An EEG was performed and showed the findings described in the image. ...
Background
Mitochondrial DNA polymerase, which is encoded by the POLG (polymerase gamma) gene, is responsible for the replication of the mitochondrial genome. Around 300 pathogenic variants have been identified in this gene and the clinical impact of POLG mutations is highly variable in both severity and phenotype. Our case had a clinical presentation distinct from the known mitochondrial syndromes associated with POLG gene, in the form of refractory focal seizures against a background of progressive ataxia, late symptom onset and rapid progression. In addition, our patient had signal changes in the pons with a unique radiological feature not previously described in this disease.
Case presentation
We describe a 46-year-old lady with adult onset refractory focal seizures against a background of progressive cognitive impairment and ataxia preceded by a febrile illness. MRI brain showed T2/FLAIR hyperintensities involving right frontal and parietal cortex, bilateral thalamus, pons and cerebellum. Clinical exome and mitochondrial genome sequencing identified homozygous missense variation in exon 13 of the POLG gene. Among these above radiological features, a novel radiological finding in a case of POLG mutation was the transverse pontine signal change, which has not been described till date to our knowledge. She was being treated and given increasing doses and combinations of anti-seizure medications, but succumbed to the illness after two months.
Conclusions
This case highlights a unique radiological finding in the form of transverse T2/FLAIR signal change in pons, in a case of genetically proven case of POLG mutation along with other common radiological features. The triad of clinical features, which were characterised by progressive ataxia, cognitive impairment and refractory focal seizures occurring in combination, were unusual in a middle aged lady with POLG mutation.
... Consistent with these pleiotropic functions, aberrant mitochondrial activities have been linked to several human disorders, including metabolic syndromes and neurodegenerative diseases. However, while the genetic link between mitochondria, inherited neuropathies and metabolic disorders is well-described and widely observed in clinical practice and experimental biology [38][39][40][41][42], a conclusive causal connection between mitochondria and AD is less well defined, especially if compared to other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) [43][44][45][46][47]. Recent clinical findings have reported that missense mutations in the gene encoding pitrilysin metallopeptidase 1 (PITRM1, also known as presequence protease) may cause the accumulation of Aβ-positive deposits [48][49][50]. A study of a single Norwegian family revealed that patients carrying pathogenic PITRM1 mutations develop progressive spinocerebellar ataxia and functional changes of mitochondrial bioenergetics in muscle biopsy. ...
Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative diseases and accounts for the majority of dementia cases worldwide. Tremendous ongoing efforts of basic and clinical research have expanded our knowledge on AD and its complex multifactorial pathogenesis. For sporadic AD, it is widely assumed that silent and early symptomatic stages initiate decades before the irreversible decline in cognitive abilities that ultimately lead to debilitating conditions. In addition to amyloid plaques and tau-containing neurofibrillary tangles as the most prominent hallmarks of AD lesions within the affected brain areas, we now possess a broader collection of pathological signatures that are associated with AD development and progression. In this regard, there is a substantial body of evidence suggesting that hypometabolism occurs in the brains of individuals at the prodromal stage before dementia is diagnosed, which may reflect an early role of metabolic dysfunction in AD. This perspective surveys the vast literature and critically assesses the current evidence demonstrating a mitochondrial contribution to AD. Additionally, we discuss our interpretations of the reported mitochondrial signatures and consider how altered mitochondrial bioenergetics may be an additional risk factor for AD pathogenesis.
... 12 The net biological consequences of ATPase defects may quite differ from those of respiratory chain defects (for an overview of associated clinical syndromes see Goldstein et al and Zeviani and Viscomi). 32,48 In dopaminergic cells, complex I-IV defects impair ATP production, increase reactive oxygen species (ROS) formation, and induce cell death. A selective functional inhibition of ATPase results in ATP depletion, but not in enhanced ROS production or apoptosis. ...
... In the two main neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), it is becoming evident that mitochondrial alterations contribute to oxidative stress and neuronal death [6][7][8][9]. As depicted in Figure 1, angiotensin receptors are located on the cell surface, but they are also present in mitochondrial membranes [2,10,11], thus implying that RAS peptides have a direct role in regulating mitochondrial events. ...
The renin angiotensin system (RAS) has several components including signaling peptides, enzymes, and membrane receptors. The effort in characterizing this system in the periphery has led to the approval of a class of antihypertensives. Much less is known about RAS in the central nervous system. The production of RAS peptides and the expression of several RAS enzymes and receptors in dopaminergic neurons of the substantia nigra has raised expectations in the therapy of Parkinson’s disease, a neurodegenerative condition characterized by lack of dopamine in the striatum, the motor control region of the mammalian brain. On the one hand, dopamine production requires reducing power. On the other hand, reducing power is required by mechanisms involved in REDOX homeostasis. This review focuses on the potential role of RAS in the regulation of neuronal/glial expression of glucose-6-phosphate dehydrogenase, which produces the NADPH required for dopamine synthesis and for reactive oxygen species (ROS) detoxification. It is known that transgenic expression of the gene coding for glucose-6-phosphate dehydrogenase prevents the death of dopaminergic nigral neurons. Signaling via angiotensin II G protein-coupled receptors, AT1 or AT2, leads to the activation of protein kinase A and/or protein kinase C that in turn can regulate glucose-6- phosphate dehydrogenase activity, by Ser/Thr phosphorylation/dephosphorylation events. Long-term effects of AT1 or AT2 receptor activation may also impact on the concentration of the enzyme via activation of transcription factors that participate in the regulation of gene expression in neurons (or glia). Future research is needed to determine how the system can be pharmacologically manipulated to increase the availability of NADPH to neurons degenerating in Parkinson’s disease and to neuroprotective glia.
... Childhood dementia can be a component of at least 12 clinical categories of mitochondrial disease (Supplementary Table 1) and can be caused by pathogenic variants in more than half of the over 300 genes known to underlie mitochondrial disease. [6][7][8] Leigh syndrome alone can be caused by pathogenic variants in one of more than 89 different genes (both in the nuclear and mitochondrial genome). 9 Consequently, published data were supplemented with diagnostic frequency and relevant genotype-phenotype data obtained from the Australian Laboratory that has acted as the major national referral laboratory for paediatric mitochondrial disease for several decades (updated from their previous epidemiological study, 10 David Thorburn, 2020, personal communication). ...
Childhood dementia is a devastating and under-recognised group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden.
A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled.
One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100,000 (1 in 2,900 births), median life expectancy of 9 years and prevalence of 5.3 per 100,000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100,000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/).
We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.
... In humans, drastic changes can appear at the level of heteroplasmy in the next generation. These could either be mitochondrially transmitted adaptations or mtDNA copy numbers that flow from one generation to the following via the female germ line (Rai et al., 2018;Maude et al., 2019;Zeviani and Viscomi, 2022). ...
... In basal conditions, neurons and astrocytes will use the same amount of energy sources. Although neurons synthesize ATP through OXPHOS, astrocytes are specialized in metabolizing glucose through aerobic glycolysis, resulting in an enormous amount of lactate and pyruvate generation from glucose that can be transported to neurons by MCTs and hydrocarboxylic acid receptors 1 (HCAR1) (Sharma et al., 2019;Mani et al., 2021;Bhatti et al., 2022;Wang et al., 2022c;Zeviani and Viscomi, 2022). ...
Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.
... The ability of melatonin to reduce cellular proliferation in the SVZ [198] may also have implications for the initiation of the highly malignant and aggressive tumor, glioblastoma (grade 4 astrocytoma). This tumor type most often occurs in the elderly, subjects in which the nocturnal rise in melatonin is commonly severely dampened [62,95,130]. ...
... Healthy mitochondria are a requirement for optimal bioenergetics of neurons and glia as well as for maintaining redox homeostasis and proper cellular signaling functions [198]. The neural accumulation of amyloid-β and p-tau compromises mitochondrial physiology, which contributes to the pathophysiological characteristics of AD. ...
The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-β peptide (Aβ) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer’s disease (AD) defers Aβ accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.
... Mitochondrial diseases are a set of highly heterogeneous disorders caused by mutations in either nuclear or mitochondrial genes that primarily affect oxidative phosphorylation and ATP synthesis. These conditions are the most common group of inherited metabolic diseases and one of the most common types of neurological disorders [260][261][262]. In fact, most mitochondrial disease patients present prominent neurologic and myopathic disorders [263]. ...
Neurodegenerative diseases are characterized by the progressive loss of neurons, synapses, dendrites, and myelin in the central and/or peripheral nervous system. Actual therapeutic options for patients are scarce and merely palliative. Although they affect millions of patients worldwide, the molecular mechanisms underlying these conditions remain unclear. Mitochondrial dysfunction is generally found in neurodegenerative diseases and is believed to be involved in the pathomechanisms of these disorders. Therefore, therapies aiming to improve mitochondrial function are promising approaches for neurodegeneration. Although mitochondrial-targeted treatments are limited, new research findings have unraveled the therapeutic potential of several groups of antibiotics. These drugs possess pleiotropic effects beyond their anti-microbial activity, such as anti-inflammatory or mitochondrial enhancer function. In this review, we will discuss the controversial use of antibiotics as potential therapies in neurodegenerative diseases.
