Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0599766 (
functional recovery
)
13,441
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
1
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
1
and V
0
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.
...
PMID:Chemical screening identifies ATM as a target for alleviating senescence. 2834 4
