The Role of Mitochondria in the Aging Processes of Yeast

Breitenbach, Michael; Laun, Peter; Dickinson, J. Richard; Klocker, Andrea; Rinnerthaler, Mark; Dawes, Ian W.; Aung-Htut, May T.; Breitenbach-Koller, Hannelore; Caballero, Antonio; Nyström, Thomas; Büttner, Sabrina; Eisenberg, Tobias; Madeo, Frank; Ralser, Markus

doi:10.1007/978-94-007-2561-4_3

Cited by 47 publications

(45 citation statements)

References 120 publications

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“…The extension of CLS depends on the existence of an intact respiratory metabolism 38394041 and also by the expression of intact antioxidant defenses 424344. Given that these requirements are affected in cells expressing both Coq7-pAAA and Coq7-pDED, CLS have been measured in these cells (Figure 3A and Table S1).…”

Section: Resultsmentioning

confidence: 99%

Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast

et al. 2017

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Coenzyme Q is an essential lipid with redox capacity that is present in all organisms. In yeast its biosynthesis depends on a multiprotein complex in which Coq7 protein has both catalytic and regulatory functions. Coq7 modulates CoQ6 levels through a phosphorylation cycle, where dephosphorylation of three amino acids (Ser/Thr) by the mitochondrial phosphatase Ptc7 increases the levels of CoQ6. Here we analyzed the role of Ptc7 and the phosphorylation state of Coq7 in yeast mitochondrial function. The conversion of the three Ser/Thr to alanine led to a permanently active form of Coq7 that caused a 2.5-fold increase of CoQ6 levels, albeit decreased mitochondrial respiratory chain activity and oxidative stress resistance capacity. This resulted in an increase in endogenous ROS production and shortened the chronological life span (CLS) compared to wild type. The null PTC7 mutant (ptc7∆) strain showed a lower biosynthesis rate of CoQ6 and a significant shortening of the CLS. The reduced CLS observed in ptc7Δ was restored by the overexpression of PTC7 but not by the addition of exogenous CoQ6. Overexpression of PTC7 increased mitophagy in a wild type strain. This finding suggests an additional Ptc7 function beyond the regulation of CoQ biosynthesis. Genetic disruption of PTC7 prevented mitophagy activation in conditions of nitrogen deprivation. In brief, we show that, in yeast, Ptc7 modulates the adaptation to respiratory metabolism by dephosphorylating Coq7 to supply newly synthesized CoQ6, and by activating mitophagy to remove defective mitochondria at stationary phase, guaranteeing a proper CLS in yeast.

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Section: Resultsmentioning

confidence: 99%

Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast

et al. 2017

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“…1,26 To test whether mitochondria mediate D 2 O-promoted longevity, we conducted CLS assays on yeast strains with mitochondrial deficiency. The mip1Δ strain carries deletion of the gene encoding the sole yeast mitochondrial DNA polymerase gamma subunit 27 and are short-lived (39.4% reduction in mean CLS versus wild type, P <1E−10; Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

Yeast longevity promoted by reversing aging-associated decline in heavy isotope content

2016

npj Aging Mech Dis

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Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity.

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“…As mitochondria are the major source of reactive oxygen species, mtDNA may be vulnerable to oxidative damage (Harman, 1956). The mitochondrial genome has a higher mutation rate than the nuclear genome (Lynch et al ., 2008), and the biology of yeast mitochondria has been implicated in aging (Breitenbach et al ., 2012). We found that mtDNA was consistently lost in WT cells after they generated 10–20 daughter cells, and this effect was also seen in young cells after several aging cycles, making many of these cells respiration deficient (Fig 3…”

Section: Resultsmentioning

confidence: 99%

Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae

2015

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The concept that mutations cause aging phenotypes could not be directly tested previously due to inability to identify age-related mutations in somatic cells and determine their impact on organismal aging. Here, we subjected Saccharomyces cerevisiae to multiple rounds of replicative aging and assessed de novo mutations in daughters of mothers of different age. Mutations did increase with age, but their low numbers, < 1 per lifespan, excluded their causal role in aging. Structural genome changes also had no role. A mutant lacking thiol peroxidases had the mutation rate well above that of wild-type cells, but this did not correspond to the aging pattern, as old wild-type cells with few or no mutations were dying, whereas young mutant cells with many more mutations continued dividing. In addition, wild-type cells lost mitochondrial DNA during aging, whereas shorter-lived mutant cells preserved it, excluding a causal role of mitochondrial mutations in aging. Thus, DNA mutations do not cause aging in yeast. These findings may apply to other damage types, suggesting a causal role of cumulative damage, as opposed to individual damage types, in organismal aging.

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The Role of Mitochondria in the Aging Processes of Yeast

Cited by 47 publications

References 120 publications

Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast

Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast

Yeast longevity promoted by reversing aging-associated decline in heavy isotope content

Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae

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