MFN2 is a mitochondrial outer membrane GTPase that mediates mitochondrial fusion and clustering through formation of homotypic and heterotypic protein complexes 1. Beyond fusion, MFN2 has evolved critical regulatory roles in cellular homeostasis. It tethers the endoplasmic reticulum to mitochondria, facilitating calcium signaling and inter-organelle communication 2. MFN2 binds phosphatidylserine and promotes ER-to-mitochondrial phospholipid transfer, essential for mitochondrial membrane synthesis and metabolic function 3. MFN2 coordinates glycolysis with oxidative phosphorylation through interaction with PKM2, a key regulatory axis in cancer metabolism 4. The protein is required for efficient mitophagy via PRKN recruitment and quality control of dysfunctional mitochondria 5. MFN2 dysfunction causes hereditary neuropathies including Charcot-Marie-Tooth disease type 2A 5. MFN2 deficiency triggers non-alcoholic fatty liver disease (NASH) through disrupted ER-mitochondrial phospholipid homeostasis and ER stress 3. Enhanced MFN2-mediated mitochondria-ER contact improves CD8+ T cell metabolic fitness and anti-tumor immunity 6. Collectively, MFN2 integrates mitochondrial dynamics with metabolic signaling, calcium homeostasis, and cellular quality control.