biostudies-literatureYuan LNCATS NIH HHSNCI NIH HHS625-643https://www.ebi.ac.uk/biostudies/studies/S-EPMC5993829biostudies-literatureUnknown28(6)Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme glCell researchSwitching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death.PMC5993829R01 CA154586UL1 TR001117HuangLiu JTan MYuan LXiang HWang XFThompson JWLiu XChen XQDing YHu JHe YHKong QPZhai LQian LfalseSwitching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death.Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme gl2018-01-01T00:00:00Z2018 Jun2026-04-29T16:19:42.233Z2019-07-01T13:50:12ZS-EPMC59938292980801210.1038/s41422-018-0043-5