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An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast

Abstract

Mitochondria have a central role in ageing. They are considered to be both a target of the ageing process and a contributor to it1. Alterations in mitochondrial structure and function are evident during ageing in most eukaryotes2, but how this occurs is poorly understood. Here we identify a functional link between the lysosome-like vacuole and mitochondria in Saccharomyces cerevisiae, and show that mitochondrial dysfunction in replicatively aged yeast arises from altered vacuolar pH. We found that vacuolar acidity declines during the early asymmetric divisions of a mother cell, and that preventing this decline suppresses mitochondrial dysfunction and extends lifespan. Surprisingly, changes in vacuolar pH do not limit mitochondrial function by disrupting vacuolar protein degradation, but rather by reducing pH-dependent amino acid storage in the vacuolar lumen. We also found that calorie restriction promotes lifespan extension at least in part by increasing vacuolar acidity via conserved nutrient-sensing pathways3. Interestingly, although vacuolar acidity is reduced in aged mother cells, acidic vacuoles are regenerated in newborn daughters, coinciding with daughter cells having a renewed lifespan potential4. Overall, our results identify vacuolar pH as a critical regulator of ageing and mitochondrial function, and outline a potentially conserved mechanism by which calorie restriction delays the ageing process. Because the functions of the vacuole are highly conserved throughout evolution5, we propose that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.

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Figure 1: Age-induced mitochondrial dysfunction is suppressed by VMA1 overexpression.
Figure 2: Vacuolar acidity is reduced in ageing cells and regulates mitochondrial function and lifespan.
Figure 3: Reduced vacuolar acidity causes mitochondrial dysfunction by disrupting amino acid homeostasis.
Figure 4: Calorie restriction extends lifespan by regulating vacuolar acidity.

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Acknowledgements

We thank L. Pallanck and members of the Gottschling laboratory for reviewing the manuscript; K. Henderson for helpful discussions; G. Miesenbock, D. Lindstrom and J. Hsu for reagents; and L. Dimitrov for technical assistance. This work was supported by National Institutes of Health grants AG037512 and AG023779, and a Glenn Award for Research in Biological Mechanisms of Aging to D.E.G., and by fellowships from the Helen Hay Whitney Foundation and Genetic Approaches to Aging Training Grant (T32 AG000057) to A.L.H.

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A.L.H. designed and carried out the experiments. D.E.G. provided experimental guidance and supervision. Both authors discussed the results and implications of the experiments. The paper was written by A.L.H. and edited by D.E.G.

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Correspondence to Daniel E. Gottschling.

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Hughes, A., Gottschling, D. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012). https://doi.org/10.1038/nature11654

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