Mitochondria-lysosome coupling contributes to lysosome acidification and aging

Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defect in lysosome/vacuole acidification is a conserved hallmark of aging and age-related diseases. Traditionally, lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. In this study, we uncovered a previously unrecognized, conserved lysosome/vacuole acidification mechanism, involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through membrane contacts between mitochondria and lysosomes/vacuoles. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by expressing a linker to connect these organelles and through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and enhances autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.