Well-Aging Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon, Korea.
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Nat Chem Biol. 2017 Jun;13(6):616-623. doi: 10.1038/nchembio.2342. Epub 2017 Mar 27.
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.
衰老，定义为不可逆的细胞周期停滞，是衰老和与年龄相关疾病的主要驱动力。在这里，我们进行了高通量筛选，以鉴定能缓解衰老的化合物，并确定了共济失调毛细血管扩张突变（ATM）抑制剂 KU-60019 为一种有效的试剂。为了阐明 ATM 在衰老中的作用机制，我们进行了酵母双杂交筛选，发现 ATM 与液泡 ATP 酶 V 亚基 ATP6V1E1 和 ATP6V1G1 相互作用。具体来说，ATM 通过直接磷酸化 ATP6V1G1 来减少 E-G 二聚体的形成。减弱 ATM 活性会恢复二聚体，从而促进 V 和 V 结构域的组装，并伴随着溶酶体的再酸化。反过来，这种再酸化诱导溶酶体/自噬系统的功能恢复，并与线粒体功能恢复和代谢重编程相偶联。总之，我们的数据揭示了一个新的机制，通过这个机制，衰老受到溶酶体-线粒体轴的控制，其功能通过 ATM 活性的精细调节来调节。
