Exercise intolerance due to cytochrome <i>b</i> mutation

Massie, Rami; Wong, Lee Jun; Milone, Margherita

doi:10.1002/mus.21649

Cited by 19 publications

(9 citation statements)

References 32 publications

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“…AOX can thus complement COX deficiency sufficiently to enable muscle development but can only do so incompletely for muscle function, indicating that at least some residual proton-pumping activity at cIII/cIV is essential for full activity of the tissue. This may mirror the prominence of muscle involvement in those human mitochondrial diseases where the primary defect causes only a decrease in the activity of cIV (20) or cIII (50). …”

Section: Discussionmentioning

confidence: 91%

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency

Kemppainen

Rinne

Sriram

et al. 2013

Human Molecular Genetics

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Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.

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Section: Discussionmentioning

confidence: 91%

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency

Kemppainen

Rinne

Sriram

et al. 2013

Human Molecular Genetics

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“…Our case resembles that of several mutations in MTCYTB , another mtDNA gene that encodes for the cytochrome b , a subunit of Complex III, which are often sporadic, in which a pure myopathy with exercise intolerance has been described [9], [10], [11]. Since now only few patients showing an exclusively mild muscular phenotype have been described carrying mutations in MTND4 and MTND5 genes coding for CI [12], [13] and only one patient has been reported with a phenotype similar to our patient, characterized by severe exercise intolerance and lactic acidosis, due to a deletion of 2 bp in MTND2 gene [6].…”

Section: Discussionmentioning

confidence: 67%

Pure myopathy with enlarged mitochondria associated to a new mutation in MTND2 gene

Zanolini

Potic

Carrara

et al. 2017

Molecular Genetics and Metabolism Reports

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To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red – COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions. Biochemical assays revealed a severe isolated complex I deficiency. We identified a novel, heteroplasmic mutation m.4831G > A in the MTND2 gene, causing the p.Gly121Asp substitution in the ND2 protein. The mutation was present in the 95% of mitochondrial genomes from patient's muscle tissue, at a lower level in cells from the urinary tract and at a lowest level in lymphocytes from patient's blood; the base substitution was absent in fibroblasts and in the tissues from proband's healthy mother and brother. The specific skeletal muscle tissue involvement can explain the childhood-onset and the relatively benign, exclusively myopathic course of the disease.

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“…When skeletal muscle is affected, the term mitochondrial myopathy is used. In isolated mitochondrial myopathy without involvement of other tissues, patients can exhibit myalgia, fatigue, exercise intolerance, proximal and distal muscle weakness, and elevated serum CK [91]. Other clinical manifestations include the chronic progressive external ophthalmoplegia (CPEO), in which a slowly progressive paresis of the extra ocular muscles is the most important phenotype [92] and severe encephalomyopathy of infancy or childhood, in which brain and skeletal muscle tissue are involved, producing marked hypotonia, respiratory muscle weakness, and feeding difficulty [93].…”

Section: Mitochondrial Myopathiesmentioning

confidence: 99%

Hereditary Myopathies

González‐Jamett¹,

Bevilacqua²,

Díaz³

2018

Muscle Cell and Tissue - Current Status of Research Field

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Hereditary myopathies are inherited disorders primarily affecting the skeletal muscle tissue. These are caused by mutations in different genes-encoding proteins that play important roles in muscle structure and function. Skeletal muscle weakness and hypotonia are typical clinical manifestations in most of hereditary myopathies. Histological features such as fiber type disproportion, myofibrillar disorganization, and structural abnormalities are usually observed in muscle biopsies of non-dystrophic myopathies, while fibrosis, fiber regeneration, wasting, and atrophy are characteristic of dystrophic myopathies. However, similar histopathological features may overlap in different hereditary myopathies. This is how mutations in a same gene can lead to different forms of hereditary myopathies and a same myopathic phenotype can derive from defects in different related genes making difficult a specific diagnosis. In this regard, understanding all aspects of hereditary myopathies can facilitate a better diagnosis and treatment. In this chapter, we offer a review of some of the most prevalent hereditary myopathies, highlighting clinical, histological, and molecular aspects of these muscle disorders.

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Exercise intolerance due to cytochrome b mutation

Cited by 19 publications

References 32 publications

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency

Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency

Pure myopathy with enlarged mitochondria associated to a new mutation in MTND2 gene

Hereditary Myopathies

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