MIEF2 (mitochondrial elongation factor 2) is a mitochondrial outer membrane protein that functions as a critical regulator of mitochondrial fission. MIEF2 promotes the recruitment and association of the dynamin-related protein 1 (DRP1/DNM1L) to the mitochondrial surface through multivalent interactions, operating independently of FIS1 and MFF proteins, and regulates DRP1 GTPase activity 1. This fission regulation integrates multiple cellular signals: soft extracellular matrices enhance MIEF2-dependent fission through increased peri-mitochondrial F-actin, promoting reactive oxygen species production and NRF2-mediated antioxidant responses 2. MIEF2 expression is dynamically regulated by the E3 ubiquitin ligase MARCH5, which mediates its proteasomal degradation; this degradation pathway protects against hepatic steatosis and excessive mitochondrial fission in alcoholic liver disease 3. Additionally, FoxO transcription factors regulate MIEF2 at transcriptional and post-translational levels to control mitochondrial homeostasis 4. Beyond fission, MIEF2 participates in mitochondrial quality control mechanisms, including mitochondrial-derived vesicle biogenesis and mitophagy pathways 5. Dysregulation of MIEF2 is associated with combined oxidative phosphorylation deficiency 49 and contributes to pathological conditions including cancer metastasis and osteoarthritis 6. Understanding MIEF2 regulation offers therapeutic potential for diseases involving mitochondrial dysfunction.