MUL1 is a mitochondrial E3 ubiquitin ligase that regulates multiple cellular processes through protein modification and degradation. At physiological concentrations, MUL1 functions preferentially as a SUMO E3 ligase, catalyzing SUMOylation of substrates including DNM1L and NDP52, while also exerting weak K48-linked ubiquitin ligase activity toward targets such as AKT1 and cytoplasmic TP53, targeting them for proteasomal degradation. MUL1 controls mitochondrial morphology by promoting fission through negative regulation of the fusion proteins MFN1 and MFN2, operating in a pathway parallel to PINK1/PRKN. Under mitochondrial stress, the MUL1-MFN2 pathway maintains mitochondrial integrity and restrains mitophagy in early neurodegeneration. MUL1-mediated SUMOylation of Drp1 stabilizes ER/mitochondrial contact sites required for apoptotic cytochrome c release, and SUMOylation of NDP52 regulates mitophagy in radiation-induced cardiac injury. In cancer, MUL1 acts as a tumor suppressor: it mediates HIF-2α and HIF-1α degradation in clear cell renal cell carcinoma and osteosarcoma respectively, and promotes HSPA9 SUMOylation and export from mitochondria to suppress lymph node metastasis in bladder cancer. MUL1 also inhibits TBK1 in head and neck cancer, reducing stress granule-mediated cytoprotection. Additionally, MUL1 suppresses antiviral responses by mediating RIG-I sumoylation. Genetic variants in MUL1 associate with Parkinson's disease risk in Chinese cohorts.