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V-type proton ATPase subunit G 1 (V-ATPase subunit G 1) (V-ATPase 13 kDa subunit 1) (Vacuolar proton pump subunit G 1) (Vacuolar proton pump subunit M16) [ATP6G] [ATP6G1] [ATP6J]


Chemical screening identifies ATM as a target for alleviating senescence.

Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V and V domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.

MeSH Terms

  • Adenosine Triphosphatases
  • Aging
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Nucleus
  • Drug Delivery Systems
  • Enzyme Activation
  • Flow Cytometry
  • Humans
  • Hydrogen-Ion Concentration
  • Lysosomes
  • Mice
  • Mitochondria
  • Morpholines
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Thioxanthenes