Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, themolecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, andthe specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuliremain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processingmachinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed duringthe mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates,mitochondrial metabolic enzyme glycerol-3-phosphate dehydrogenase (GPD2) and cell death regulator apoptosis-inducing factor(AIF). For cells destined to senesce, concerted shutdown of the IMMP2L-GPD2 and IMMP2L-AIF signaling axes collaboratively drivesthe senescent process by reprogramming mitochondria-associated redox status, phospholipid metabolism and signaling network,and simultaneously blocking cell death under oxidative stress conditions.