ATP6V1G1
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]
PublicationsПравить
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