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Neurotherapeutics : the Journal of the... Oct 2018Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation (OXPHOS) in the mitochondria. This causes a... (Review)
Review
Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation (OXPHOS) in the mitochondria. This causes a deficit in energy production in the form of adenosine triphosphate (ATP), particularly in skeletal muscle. The diagnosis of mitochondrial myopathy is reliant on the combination of numerous techniques including traditional histochemical, immunohistochemical, and biochemical testing combined with the fast-emerging molecular genetic techniques, namely next-generation sequencing (NGS). This has allowed for the diagnosis to become more effective in terms of determining causative or novel genes. However, there are currently no effective or disease-modifying treatments available for the vast majority of patients with mitochondrial myopathies. Existing therapeutic options focus on the symptomatic management of disease manifestations. An increasing number of clinical trials have investigated the therapeutic effects of various vitamins, cofactors, and small molecules, though these trials have failed to show definitive outcome measures for clinical practice thus far. In addition, new molecular strategies, specifically mtZFNs and mtTALENs, that cause beneficial heteroplasmic shifts in cell lines harboring varying pathogenic mtDNA mutations offer hope for the future. Moreover, recent developments in the reproductive options for patients with mitochondrial myopathies mean that for some families, the possibility of preventing transmission of the mutation to the next generation is now possible.
Topics: Adenosine Triphosphate; Humans; Mitochondrial Myopathies; Muscle, Skeletal
PubMed: 30406383
DOI: 10.1007/s13311-018-00674-4 -
Arquivos de Neuro-psiquiatria Nov 2015Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical... (Review)
Review
Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.
Topics: Biopsy; Diagnosis, Differential; Humans; MELAS Syndrome; Magnetic Resonance Imaging; Mutation
PubMed: 26517220
DOI: 10.1590/0004-282X20150154 -
Nature Reviews. Cardiology Apr 2017Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition... (Review)
Review
Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
Topics: Consensus; Drug Discovery; Electron Transport; Heart Failure; Humans; Kearns-Sayre Syndrome; Mitochondria, Heart; Mitochondrial Myopathies; Prognosis
PubMed: 28004807
DOI: 10.1038/nrcardio.2016.203 -
Cell Metabolism Jun 2020NAD is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD depletion occurs...
NAD is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD depletion occurs in patients with degenerative disorders and whether NAD repletion improves their symptoms has remained open. Here, we report systemic NAD deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD-booster niacin, a vitamin B3 form (to 750-1,000 mg/day; clinicaltrials.govNCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD increased in all subjects, up to 8-fold, and muscle NAD of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD deficiency and points niacin to be an efficient NAD booster for treating mitochondrial myopathy.
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Mitochondrial Myopathies; Muscles; NAD; Niacin; Young Adult
PubMed: 32386566
DOI: 10.1016/j.cmet.2020.04.008 -
Neurotherapeutics : the Journal of the... Apr 2013Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a... (Review)
Review
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.
Topics: DNA Replication; DNA, Mitochondrial; Humans; Liver Transplantation; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Mutation; Nervous System Diseases; Nucleotides; Nutritional Support; Thymidine
PubMed: 23385875
DOI: 10.1007/s13311-013-0177-6 -
Journal of Korean Medical Science Nov 2017
Topics: Arabinofuranosyluracil; Humans; Mitochondria; Mitochondrial Myopathies; Muscular Diseases
PubMed: 28960021
DOI: 10.3346/jkms.2017.32.11.1732 -
The Journal of Clinical Investigation Jul 2022Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we...
Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knockin (KI) mouse model and found that mutant CHCHD10 aggregated in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, the survival of CHCHD10-KI mice depended on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 was critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.
Topics: Animals; Metalloproteases; Mice; Mitochondria; Mitochondrial Membranes; Mitochondrial Myopathies; Mitochondrial Proteins; Mutation; Protein Folding
PubMed: 35700042
DOI: 10.1172/JCI157504 -
Circulation Research May 2021[Figure: see text].
[Figure: see text].
Topics: Acetylation; Acyl-CoA Dehydrogenase; Animals; Disease Models, Animal; Down-Regulation; Fatty Acids; Heart Failure, Diastolic; Humans; Ketone Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Myopathies; NAD; Niacinamide; Oxidation-Reduction; Oxygen Consumption; Pyridinium Compounds; Sirtuin 3
PubMed: 33882692
DOI: 10.1161/CIRCRESAHA.120.317046 -
The Biochemical Journal Nov 2023Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in... (Review)
Review
Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.
Topics: Humans; Muscle, Skeletal; Mitochondrial Myopathies; Mitochondria; Mitochondrial Turnover; Biology
PubMed: 37965929
DOI: 10.1042/BCJ20220233 -
Current Opinion in Neurology Oct 2019Although mitochondrial diseases impose a significant functional limitation in the lives of patients, treatment of these conditions has been limited to dietary... (Review)
Review
PURPOSE OF REVIEW
Although mitochondrial diseases impose a significant functional limitation in the lives of patients, treatment of these conditions has been limited to dietary supplements, exercise, and physical therapy. In the past few years, however, translational medicine has identified potential therapies for these patients.
RECENT FINDINGS
For patients with primary mitochondrial myopathies, preliminary phase I and II multicenter clinical trials of elamipretide indicate safety and suggest improvement in 6-min walk test (6MWT) performance and fatigue scales. In addition, for thymidine kinase 2-deficient (TK2d) myopathy, compassionate-use oral administration of pyrimidine deoxynucleosides have shown preliminary evidence of safety and efficacy in survival of early onset patients and motor functions relative to historical TK2d controls.
SUMMARY
The prospects of effective therapies that improve the quality of life for patients with mitochondrial myopathy underscore the necessity for definitive diagnoses natural history studies for better understanding of the diseases.
Topics: Clinical Trials as Topic; Exercise; Fatigue; Humans; Mitochondrial Myopathies; Oligopeptides; Quality of Life
PubMed: 31408013
DOI: 10.1097/WCO.0000000000000743