Reversal of a mitochondrial DNA defect in human skeletal muscle

Clark, Kristi; Bindoff, Laurence A.; Lightowlers, Robert N.; Andrews, Richard M.; Griffiths, Philip G.; Johnson, Margaret; Brierley, Elizabeth J.; Turnbull, Douglass M.

doi:10.1038/ng0797-222

Cited by 132 publications

(71 citation statements)

References 13 publications

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“…Lowering even partially the mutation load could therefore significantly improve the phenotype. Several attempts have been done towards that direction either targeting the replication of the mutant mitochondrial DNA in cellular or animal models [18,19] or selecting for cells with lower mutation load in cellular models and in patients [20][21][22]. Although establishing the proof of principle these attempts have yet too show their efficacy on a broader field.…”

Section: Most Deleterious Mtdna Mutations Only Induce Defects When Prmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed.Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

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Section: Most Deleterious Mtdna Mutations Only Induce Defects When Prmentioning

confidence: 99%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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“…Preliminary studies injecting bupivacaine hydrochloride (0.75%) to induce muscle necrosis showed satellite cell proliferation exclusively responsible for the derivation of new muscle fibers and an improvement in biochemical activity. 11,82 Taivassalo et al 86 found an unequivocal decrease in the proportion of COX-negative fibers after concentric training, with an absolute reduction in the number of fibers with mutant mtDNA.…”

Section: Resistance Trainingmentioning

confidence: 98%

“…10 These figures suggest that mtDNA disease is a common cause of chronic morbidity and is more prevalent than previously thought. This not only has implications for allocation of health care resources, but also highlights the need to develop new approaches to the clinical management of patients 11 with mitochondrial disease.…”

Section: Frequency and Natural Course Of Mitochondrial Diseasesmentioning

confidence: 99%

“…Because satellite cells frequently carry a lower rate of mutant or sometimes no mutation at all, this technique may prove useful in reducing the heteroplasmy of a pathogenic mutation by gene shifting. 81 Muscle regeneration can be induced by injections of substances into muscle (bupivacaine) 11,82 or by isometric exercise causing microtraumas. 84 In support of this, in one patient carrying a nonsense mutation in the COX I gene, recurrent myoglobinuria led to a positive selection of COX positive fibers harboring no mutant mtDNA.…”

Section: Inducing Muscle Regenerationmentioning

confidence: 99%

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How Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy

2008

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Summary:Mitochondrial disorders are a heterogeneous group of diseases affecting different organs (brain, muscle, liver, and heart), and the severity of the disease is highly variable. The chronicity and heterogeneity, both clinically and genetically, means that many patients require surveillance follow-up over their lifetime, often involving multiple disciplines. Although our understanding of the genetic defects and their pathological impact underlying mitochondrial diseases has increased over the past decade, this has not been paralleled with regards to treatment. Currently, no definitive pharmacological treatment exists for patients with mitochondrial dysfunction, except for patients with primary deficiency of coenzyme Q10. Pharmacological and nonpharmacological treatments increasingly being investigated include ketogenic diet, exercise, and gene therapy. Management is aimed primarily at minimizing disability, preventing complications, and providing prognostic information and genetic counseling based on current best practice. Here, we evaluate therapies used previously and review current and future treatment modalities for both adults and children with mitochondrial disease.

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“…However, gene therapy on defective gene itself is thought as the ultimate way of treating the disease after all. [30][31][32][33] …”

Section: Diagnosis and Treatment Of Mitochondrial Diseasesmentioning

confidence: 99%