Homeostatic mitochondrial lipid peroxidation governs mitochondrial fission site selection and daughter mitochondrial fate

Mitochondrial fission is essential for cellular homeostasis, yet signals that license specific sites for division and link fission to subsequent fate remain largely elusive. Here, we identify homeostatic inner mitochondrial membrane lipid peroxidation (IMM LPO) as an upstream signal coordinating these two fundamental processes. We show, during homeostatic conditions, a focal IMM LPO increase is necessary for division, marking mitochondria-ER contacts (MERCS) for fission. IMM LPO and MERCS formation can precede one another, engaging in a positive feedback loop: focal IMM LPO promotes ER recruitment and subsequent mitochondrial Ca²⁺ influx, which in turn accelerates IMM LPO, creating a robust commitment for division. Critically, the magnitude of the IMM LPO signal at the prospective fission site dictates daughter mitochondrial fate. Modest LPO generates healthy daughter mitochondria, while severe LPO targets depolarized daughters for mitophagy. This IMM LPO-mediated fission is a general mechanism, exhibiting hyperactivation in prostate cancer. Our study defines a fundamental initiation event for mitochondrial fission, establishing homeostatic IMM LPO as a signal that integrates fission site selection with mitochondrial fate.