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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 -
Annals of Medicine Feb 2013Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active,... (Review)
Review
Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active, and therefore myopathy is a common element of the clinical presentation of these disorders, although this may be overshadowed by central neurological features. This review is aimed at a general medical and neurologist readership and provides a clinical approach to the recognition, investigation, and treatment of mitochondrial myopathies. Emphasis is placed on practical management considerations while including some recent updates in the field.
Topics: Biopsy; Cytochrome-c Oxidase Deficiency; Deglutition Disorders; Dietary Supplements; Endocrine System Diseases; Exercise Test; Exercise Therapy; Hearing Disorders; Heart Diseases; Humans; Mitochondrial Myopathies; Muscle, Skeletal; Ubiquinone; Vision Disorders; Vitamins
PubMed: 21867371
DOI: 10.3109/07853890.2011.605389 -
Pediatric Nephrology (Berlin, Germany) Jan 2021Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria.... (Review)
Review
Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Topics: DNA, Mitochondrial; Humans; Kearns-Sayre Syndrome; Mitochondria; Mitochondrial Myopathies; Mutation; Nephritis, Interstitial
PubMed: 31925537
DOI: 10.1007/s00467-019-04404-6 -
Journal of Neurology Dec 2022To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
OBJECTIVES
To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
METHODS
Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.
RESULTS
At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.
CONCLUSIONS
PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.
Topics: Humans; Follow-Up Studies; Walk Test; Mitochondrial Myopathies; Ophthalmoplegia, Chronic Progressive External; Time Factors; Walking
PubMed: 35980466
DOI: 10.1007/s00415-022-11324-3 -
Journal of Neuromuscular Diseases 2022Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders.... (Review)
Review
Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.
Topics: Animals; Child; DNA, Mitochondrial; Humans; Mice; Mitochondrial Myopathies; Muscular Diseases; Thymidine Kinase
PubMed: 35094997
DOI: 10.3233/JND-210786 -
Developmental Disabilities Research... 2010Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and... (Review)
Review
Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ(10) is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ(10) supplementation. CoQ(10) deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ(10) deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies.
Topics: Atrophy; Cerebellum; Child; Chromosome Aberrations; DNA Mutational Analysis; Developmental Disabilities; Disease Progression; Genes, Recessive; Humans; Infant, Newborn; Kidney Diseases; Kidney Glomerulus; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Spinocerebellar Degenerations; Ubiquinone
PubMed: 20818733
DOI: 10.1002/ddrr.108 -
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 -
Circulation Oct 2012
Topics: Cardiomyopathies; Exercise Test; Forecasting; Heart Diseases; Humans; Mitochondrial Myopathies; Oxygen Consumption; Patients; Prognosis; Records; Respiratory Function Tests; Respiratory Tract Diseases; Software
PubMed: 22952317
DOI: 10.1161/CIR.0b013e31826fb946 -
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 -
International Journal of Molecular... Sep 2022Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and...
Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype.
Topics: DNA, Mitochondrial; Electron Transport Complex IV; Humans; Mitochondrial Myopathies; Muscle, Skeletal; Myocardium; Succinate Dehydrogenase; Thymidine Kinase
PubMed: 36232299
DOI: 10.3390/ijms231911002