title: Chemical screening identifies ATM as a target for alleviating senescence.
abstract: 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 V1subunits 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 V1and V0domains 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.
authors.affiliation: Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Kang
authors.affiliation: Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
authors.forename: Joon Tae
authors.initials: JT
authors.lastname: Park
authors.affiliation: Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
authors.forename: Kobong
authors.initials: K
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yongsub
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
authors.forename: Hyo Jei Claudia
authors.initials: HJC
authors.lastname: Choi
authors.affiliation: Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Jung
authors.affiliation: Department of New Biology, DGIST, Daegu, Korea.
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Well Aging Research Center, DGIST, Daegu, Korea.|Department of New Biology, DGIST, Daegu, Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Park
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000375:Aging / Q000187:drug effects*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002467:Cell Nucleus; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013892:Thioxanthenes / Q000494:pharmacology*
chemical_list: C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013892:Thioxanthenes; D064007:Ataxia Telangiectasia Mutated Proteins; D000251:Adenosine Triphosphatases