MARCHF5 (membrane-associated ring-CH-type finger 5) is a mitochondrial E3 ubiquitin ligase that regulates multiple cellular processes through protein ubiquitination. Primary functions include controlling mitochondrial dynamics, apoptosis, and organellar biogenesis. MARCHF5 catalyzes K48-linked ubiquitination to promote degradation of target proteins including MIC60 1, ACC2 2, and BAK 3, while also mediating K27-linked polyubiquitination of viral proteins during infection. Mechanistically, MARCHF5 localizes to the outer mitochondrial membrane and peroxisomes, where it regulates protein stability and organellar dynamics 45. MARCHF5 is itself degraded via chaperone-mediated autophagy, controlling mitochondrial fission and protecting against oxidative stress 6. In disease contexts, MARCHF5 promotes cGAS degradation in systemic lupus erythematosus by blocking lactate-mediated cGAS lactylation, thereby suppressing interferon responses 7. MARCHF5 also enhances BAK-mediated apoptosis independently of BH3-only proteins 3 and drives ovarian cancer progression through ACC2 degradation-enhanced fatty acid oxidation 2. These diverse functions position MARCHF5 as a critical node in mitochondrial quality control and immune regulation with implications for cancer and autoimmune disease.