Mitochondrial threshold effects

Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean‐Pierre; Letellier, Thierry

doi:10.1042/bj20021594

Cited by 702 publications

(615 citation statements)

References 137 publications

(145 reference statements)

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“…The underlying cause is typically a mutation in either a nuclear gene encoding a mitochondrial protein or a mitochondrial DNA (mtDNA) mutation, although most of the mutations were identified in mtDNA. 4 Currently, over 200 mtDNA mutations have been associated with defined clinical phenotypes (http://www.mitomap.org). Mitochondrial diseases are often fatal, and no effective treatment is available for any of them.…”

Section: Introductionmentioning

confidence: 99%

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

et al. 2008

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Mitochondrial diseases are not uncommon, and may result from mutations in both nuclear and mitochondrial DNA (mtDNA). At present, only palliative therapies are available for these disorders, and interest in the development of efficient treatment protocols is high. Here, we demonstrate that in cells heteroplasmic for the T8993G mutation, which is a cause for the NARP and MILS syndromes, infection with an adenovirus, which encodes the mitochondrially targeted R.XmaI restriction endonuclease, leads to selective destruction of mutant mtDNA. This destruction proceeds in a timeand dose-dependent manner and results in cells with significantly increased rates of oxygen consumption and ATP production. The delivery of R.XmaI to mitochondria is accompanied by improvement in the ability to utilize galactose as the sole carbon source, which is a surrogate indicator of the proficiency of oxidative phosphorylation. Concurrently, the rate of lactic acid production by these cells, which is a marker of mitochondrial dysfunction, decreases. We further demonstrate that levels of phosphorylated P53 and gH2ax proteins, markers of nuclear DNA damage, do not change in response to infection with recombinant adenovirus indicating the absence of nuclear DNA damage and the relative safety of the technique. Finally, some advantages and limitations of the proposed approach are discussed.

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Section: Introductionmentioning

confidence: 99%

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

et al. 2008

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“…This indicates that mtDNA deletions are extremely rare; less than 0.1 mtDNA deletion per cell on average. Importantly, even under the strong assumption that all of these deletions are concentrated in a single cell, the mutant fraction in that cell would on average still be ~27%, well below the 60% threshold commonly assumed for physiological relevance in mammals (Rossignol et al, 2003). Furthermore, in comparison with mammals, C. elegans have been reported to be tolerant toward high levels (up to 80%) of inherited mutant mtDNA with little ill effect and can remain viable even with the homozygous loss of mitochondrial polymerase enzyme (Bratic et al, 2009; Tsang & Lemire, 2002).…”

Section: Resultsmentioning

confidence: 88%

“…We find that the apparent age‐dependent increase in mutation burden is not statistically significant and that overall burden remains low over the course of life, with on average 82 ± 9 (mean ± 1 SD over all three age groups) mutant mtDNA molecules per worm irrespective of age. This mutation burden is well below the 60% threshold where mtDNA deletions would become physiologically limiting in terms of mitochondrial energy production (Rossignol et al, 2003). Even under the extremely unlikely assumption that all mutant molecules in each worm were concentrated in a single cell, the levels of mtDNA deletion in even that single cell remain under this 60% threshold.…”

Section: Discussionmentioning

confidence: 99%

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Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

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Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.

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“…One explanation for the seemingly contradictory effects of ETC mutation and longevity is a threshold effect in which compromised mitochondrial function alters cellular function only once a critical deficiency in ATP production in reached. In the context of mitochondrial mutations that cause mitochondrial disease, the variable phenotypes that occur have been tied to a critical threshold of mutation load (approximately 80%–90%) above which the phenotypes associated with disease occur (Rossignol et al., 2003). For example, heterozygous knock‐in mice with reduced levels of DNA polymerase γ, a mitochondrial DNA proofreading enzyme, have a 30‐fold increase in mitochondrial DNA mutation load but show no deleterious phenotypes and have a normal lifespan while homozygous null mutants have a dramatic reduction in lifespan (Vermulst et al., 2007).…”

Section: Discussionmentioning

confidence: 99%

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

et al. 2018

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SummaryLoss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.

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Mitochondrial threshold effects

Cited by 702 publications

References 137 publications

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

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