FIS1 (Fission, Mitochondrial 1) is a mitochondrial outer membrane protein that plays a key role in regulating mitochondrial dynamics and cellular homeostasis. Functionally, FIS1 mediates mitochondrial fragmentation and perinuclear clustering 1, playing a minor role in recruiting the fission mediator DRP1 to mitochondrial surfaces 2. FIS1 also regulates peroxisomal fission 3 and can induce cytochrome c release leading to apoptosis 1. Mechanistically, FIS1 controls distinct mitochondrial fission outcomes: peripheral fission regulated by FIS1 directs damaged mitochondria toward mitophagy, while midzone fission enables mitochondrial proliferation 4. FIS1 recruits the GAP protein TBC1D15 to mitochondria to regulate lysosomal RAB7 GTPase activity, thereby controlling mitochondria-lysosome contacts that mark fission sites 5. Post-translational modifications of FIS1 are functionally significant: lactylation promotes excessive mitochondrial fission and apoptosis in sepsis-induced kidney injury 6, while deSUMOylation preserves endothelial mitochondrial integrity against hypoxic stress 7. Clinically, dysregulated mitochondrial dynamics involving FIS1 contribute to multiple diseases including cardiac dysfunction, inflammatory bowel disease, pulmonary hypertension, and type 2 diabetes 8910.