An Early-Age Increase in Vacuolar pH Limits Mitochondrial Function and Lifespan in Yeast

Mitochondria play a central role in ageing. They are considered to be both a target of the ageing process, as well as a contributor to it(1). Alterations in mitochondrial structure and function are evident during ageing in most eukaryotes(2), but how this occurs is poorly understood. Here, we identify a functional link between the lysosome-like vacuole and mitochondria in S. 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 show 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 pathways(3). 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 potential(4). 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 functions of the vacuole are highly conserved throughout evolution(5), we hypothesize that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.