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Medicine Jan 1998Mitochondrial respiration, the most efficient metabolic pathway devoted to energy production, is at the crosspoint of 2 quite different genetic systems, the nuclear... (Review)
Review
Mitochondrial respiration, the most efficient metabolic pathway devoted to energy production, is at the crosspoint of 2 quite different genetic systems, the nuclear genome and the mitochondrial genome (mitochondrial DNA, mtDNA). The latter encodes a few essential components of the mitochondrial respiratory chain and has unique molecular and genetic properties that account for some of the peculiar features of mitochondrial disorders. However, the perpetuation, propagation, and expression of mtDNA, the majority of the subunits of the respiratory complexes, as well as a number of genes involved in their assembly and turnover, are contained in the nuclear genome. Although mitochondrial disorders have been known for more than 30 years, a major breakthrough in their understanding has come much later, with the discovery of an impressive, ever-increasing number of mutations of mitochondrial DNA. Partial deletions or duplications of mtDNA, or maternally inherited point mutations, have been associated with well-defined clinical syndromes. However, phenotypes transmitted as mendelian traits have also been identified. These include clinical entities defined on the basis of specific biochemical defects, and also a few autosomal dominant or recessive syndromes associated with multiple deletions or tissue-specific depletion of mtDNA. Given the complexity of mitochondrial genetics and biochemistry, the clinical manifestations of mitochondrial disorders are extremely heterogenous. They range from lesions of single tissues or structures, such as the optic nerve in Leber hereditary optic neuropathy or the cochlea in maternally inherited nonsyndromic deafness, to more widespread lesions including myopathies, encephalomyopathies, cardiopathies, or complex multisystem syndromes. The recent advances in genetic studies provide both diagnostic tools and new pathogenetic insights in this rapidly expanding area of human pathology.
Topics: DNA, Mitochondrial; Gene Deletion; Humans; Mitochondrial Myopathies; Multigene Family; Phenotype; Point Mutation; RNA, Transfer
PubMed: 9465864
DOI: 10.1097/00005792-199801000-00006 -
Molecular Metabolism Oct 2022Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of...
OBJECTIVE
Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.
METHODS
This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
RESULTS
We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
CONCLUSION
Increasing NAD levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD-stimulating compounds in mitochondrial myopathies.
Topics: Adenine Nucleotide Translocator 1; Animals; Mice; Mitochondrial Myopathies; Muscle Weakness; NAD; Niacinamide; Physical Conditioning, Animal; Protein Isoforms; Pyridinium Compounds
PubMed: 35940554
DOI: 10.1016/j.molmet.2022.101560 -
Indian Journal of Pathology &... May 2022Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan... (Review)
Review
Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.
Topics: Algorithms; Heart; Humans; Infant, Newborn; Metabolism, Inborn Errors; Mitochondrial Myopathies; Muscular Diseases
PubMed: 35562160
DOI: 10.4103/ijpm.ijpm_1088_21 -
International Journal of Molecular... Dec 2022Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative... (Review)
Review
Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution of these myopathies show significant differences. However, some physiological and pathophysiological aspects of mitochondria often reveal other potential molecular mechanisms that could have a significant pathogenetic role in the clinical evolution of these disorders, such as: i. a deranged ROS production both in term of signaling and in terms of damaging molecules; ii. the severe modifications of nicotinamide adenine dinucleotide (NAD)+/NADH, pyruvate/lactate, and α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratios. A better definition of the molecular mechanisms at the basis of their pathogenesis could improve not only the clinical approach in terms of diagnosis, prognosis, and therapy of these myopathies but also deepen the knowledge of mitochondrial medicine in general.
Topics: Humans; Mitochondria; Mitochondrial Myopathies; Cell Respiration; Oxidative Phosphorylation; NAD; Reactive Oxygen Species
PubMed: 36613565
DOI: 10.3390/ijms24010124 -
Chinese Medical Journal Jul 2015Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a... (Review)
Review
OBJECTIVE
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. MELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well.
DATA SOURCES
The data used in this review came from published peer review articles from October 1984 to October 2014, which were obtained from PubMed. The search term is "MELAS".
STUDY SELECTION
Information selected from those reported studies is mainly based on the progress on clinical features, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS.
RESULTS
MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging (MRI) can provide directional information on this disease. Muscle biopsy has meaningful value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the mutation m.3243A>G of the mitochondrial transfer RNA (Leu (UUR)) gene (MT-TL1).
CONCLUSIONS
MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MRI, muscle biopsy, and genetics.
Topics: Humans; MELAS Syndrome; Magnetic Resonance Imaging
PubMed: 26112726
DOI: 10.4103/0366-6999.159360 -
Cells Mar 2022Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial...
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient's muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient's clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient's fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of variants with mitochondrial myopathy.
Topics: DNA, Mitochondrial; Endodeoxyribonucleases; Endonucleases; Humans; Mitochondria; Mitochondrial Myopathies
PubMed: 35326425
DOI: 10.3390/cells11060974 -
Cell Metabolism Aug 2017Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial...
Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.
Topics: Animals; Fibroblast Growth Factors; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Stress, Physiological
PubMed: 28768179
DOI: 10.1016/j.cmet.2017.07.007 -
Neurology Feb 2020To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.
METHODS
In cohorts of 8-13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).
RESULTS
No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.
CONCLUSIONS
Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.
CLINICALTRIALSGOV IDENTIFIER
NCT02255422.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
Topics: Adult; Anti-Inflammatory Agents; Biomarkers; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Exercise Test; Female; Heart Rate; Humans; Lactic Acid; Male; Middle Aged; Mitochondrial Myopathies; NF-E2-Related Factor 2; Treatment Outcome; Triterpenes
PubMed: 31896620
DOI: 10.1212/WNL.0000000000008861 -
Epilepsia Sep 2012The mitochondrial respiratory chain is the final common pathway for energy production. Defects affecting this pathway can give rise to disease that presents at any age... (Review)
Review
The mitochondrial respiratory chain is the final common pathway for energy production. Defects affecting this pathway can give rise to disease that presents at any age and affects any tissue. However, irrespective of genetic defect, epilepsy is common and there is a significant risk of status epilepticus. This review summarizes our current understanding of the epilepsy that occurs in mitochondrial disease, focusing on three of the most common disorders: mitochondrial myopathy encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy and ragged-red fibers (MERRF), and polymerase gamma (POLG) related disease. In addition, we review the pathogenesis and possible treatment of these disorders.
Topics: Anticonvulsants; Epilepsy; Humans; MERRF Syndrome; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies
PubMed: 22946726
DOI: 10.1111/j.1528-1167.2012.03618.x -
Scientific Reports Aug 2016Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus... (Review)
Review
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease.
Topics: Aged; Biopsy; DNA, Mitochondrial; Female; Humans; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Muscle, Skeletal; Mutation; Young Adult
PubMed: 27506553
DOI: 10.1038/srep30610