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Mitochondria-lysosome coupling contributes to lysosome acidification and aging

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292573 | GEO | 2026/03/20

REPOSITORIES: GEO

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Project description:Mitochondrial abnormalities are commonly associated with aging-related degenerative disease and the atrophy of tissues including muscle and brain. Whether bioenergetic defect is the sole pathogenic factor has been long questioned. Lysosomal damage is another hallmark of degenerative disease. However, it is unknown whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. Here, we show that mitochondrial protein import stress, which can be induced by many forms of mitochondrial injuries, causes structural and functional damage to the yeast vacuole and its mouse counterpart, the lysosome. This effect is independent of bioenergetic defects and the production of reactive oxygen species. We found that unimported mitochondrial proteins are targeted to the vacuole for degradation in yeast. Overloading by these proteins causes V-ATPase disassembly, and vacuolar deacidification, fragmentation and membrane permeabilization. In a mouse model of mitochondrial protein import stress and muscle atrophy induced by overloading of the mitochondrial protein ANT1, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, nucleotide biosynthesis, lysosomal biogenesis and iron homeostasis are activated. These signatures are recapitulated in yeast mutants of severe vacuolar damage. Supporting lysosomal dysfunction, the Ant1-transgenic muscles accumulate glycogens, lipofuscins and poorly processed multiple vesicle bodies. Multiple lysosomal repair and lysophagic pathways are activated. Luminal proteolytic enzymes including cathepsins are released into the cytosol, which likely contributes to imbalanced cellular proteostasis, reduced myofiber size and progressive muscle atrophy. In summary, we show an evolutionarily conserved pathway wherein mitochondrial defect can epistatically cause proteostatic damage to the lysosome thereby leading to tissue atrophy. This finding could help the better understanding of how the mitochondrial and lysosomal pathways of pathogenesis interact to cause degenerative disease.

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Mitochondria-lysosome coupling contributes to lysosome acidification and aging

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