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Peer-reviewedCC BYMolecular Cell

Mitochondria-lysosome coupling contributes to lysosome acidification and aging

  • Qingqing Liu1
  • Seungmin Yoo1
  • Zhixin A. Zhang1
  • Liying Li1
  • Hetian Su2
  • Lingraj Vannur1
  • Alexandra C Wooldredge1
  • Jun‐Wei B. Hughes1
  • Pierre-Yves Desprez1
  • Nan Hao2
  • Gordon J. Lithgow1
  • Julie Kay Andersen1
3 more authors
  • Malene Hansen1
  • Judith Campisi1
  • Chuankai Zhou3
  1. 1Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA
  2. 2Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA
  3. 3Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA. Electronic address: [email protected]
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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. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H + pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or 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 restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.

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Cite

BibTeXRIS
BibTeX
@article{liu2026mitochondrialysosome,
  title = {{Mitochondria-lysosome coupling contributes to lysosome acidification and aging}},
  author = {Qingqing Liu and Seungmin Yoo and Zhixin A. Zhang and Liying Li and Hetian Su and Lingraj Vannur and Alexandra C Wooldredge and Jun‐Wei B. Hughes and Pierre-Yves Desprez and Nan Hao and Gordon J. Lithgow and Julie Kay Andersen and Malene Hansen and Judith Campisi and Chuankai Zhou},
  journal = {Molecular Cell},
  year = {2026},
  month = may,
  doi = {10.1016/j.molcel.2026.05.004},
  url = {https://doi.org/10.1016/j.molcel.2026.05.004},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Mitochondria-lysosome coupling contributes to lysosome acidification and aging
AU  - Qingqing Liu
AU  - Seungmin Yoo
AU  - Zhixin A. Zhang
AU  - Liying Li
AU  - Hetian Su
AU  - Lingraj Vannur
AU  - Alexandra C Wooldredge
AU  - Jun‐Wei B. Hughes
AU  - Pierre-Yves Desprez
AU  - Nan Hao
AU  - Gordon J. Lithgow
AU  - Julie Kay Andersen
AU  - Malene Hansen
AU  - Judith Campisi
AU  - Chuankai Zhou
PY  - 2026
DA  - 2026/05/29
JO  - Molecular Cell
DO  - 10.1016/j.molcel.2026.05.004
UR  - https://doi.org/10.1016/j.molcel.2026.05.004
AB  - 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. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H + pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or 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 restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.
SN  - 1097-2765
SN  - 1097-4164
ER  -