Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function

Fayet, Guy; Jansson, Maria; Sternberg, Damien; Moslemi, Ali Reza; Blondy, Patricia; Lombès, Anne; Fardeau, Michel; Oldfors, Anders

doi:10.1016/s0960-8966(01)00332-7

Cited by 189 publications

(131 citation statements)

References 40 publications

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“…Clonal expansion, equivalent to extreme segregation, of one of these mtDNA alterations has been shown to be at the basis of the observed OXPHOS defect in muscle [27,28], colon [29] and brain [30]. These studies confirmed that the threshold mutation proportion, inducing OXPHOS defect, was very high, often close to homoplasmy.…”

Section: Clinical Observationsmentioning

confidence: 56%

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: Clinical Observationsmentioning

confidence: 56%

Unsolved issues related to human mitochondrial diseases

et al. 2014

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“…Interestingly, in the same individuals, we found a consistently higher mutation load in the Dloop, suggesting either that mutational processes are uneven across the genome, or else that some selection for fitness must occur at the cell or organelle level in vivo . As was the case for rearrangements, studies at single cell or single muscle-fibre level have revealed extensive mitotic segregation for mtDNA point mutations (Fayet et al ., 2002;Nekhaeva et al ., 2002).…”

Section: Mtdna Point Mutations and Agingmentioning

confidence: 99%

“…For example, rearranged mtDNAs found in cardiac or skeletal muscle (Brierley et al ., 1998;Bodyak et al ., 2001;Fayet et al ., 2002) commonly segregate to homoplasmy, or to high levels of heteroplasmy, resulting in demonstrable cellular dysfunction, e.g. COX-negative muscle fibre segments.…”

Section: Mtdna Rearrangements and Agingmentioning

confidence: 99%

The mitochondrial theory of aging: dead or alive?

Jacobs

2003

Aging Cell

108

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The mitochondrial theory of aging is based around the idea of a vicious cycle, in which somatic mutation of mtDNA engenders respiratory chain dysfunction, enhancing the production of DNA-damaging oxygen radicals. In turn, this is proposed to result in the accumulation of further mtDNA mutations. Finally, a bioenergetic crisis leads to overt tissue dysfunction and degeneration. A substantial body of circumstantial evidence seems to support this idea. However, the extent of detectable mtDNA mutation is far less than can easily be reconciled to this hypothesis, unless it is assumed that a subset of cells with much higher than average mtDNA mutation load is systematically lost by apoptosis. A rigorous test of the hypothesis remains to be undertaken, but would require a direct manipulation of the rate of mtDNA mutagenesis, to test whether this could alter the kinetics of aging.

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“…It is known that a critical threshold of mutated mtDNA must be reached before tissue dysfunction appears, although this mechanism is still not fully understood. Clonal expansion of mtDNA mutations has been demonstrated in aging human tissue from a number of anatomic sources (19). A recent study showed an association between the presence of clonally expanded mtDNA point mutations in colonic crypt stem cells and reduced expression of multiple electron transport chain complexes, suggesting point mutation as a potential trigger for respiratory chain alterations (20).…”

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confidence: 99%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function

Cited by 189 publications

References 40 publications

Unsolved issues related to human mitochondrial diseases

Unsolved issues related to human mitochondrial diseases

The mitochondrial theory of aging: dead or alive?

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

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