Mul1, short for mitochondrial E3 ubiquitin ligase 1, is a mitochondrial outer membrane-anchored protein. It contains transmembrane domains in its N-and C-terminal regions, with the C-terminal RING finger domain responsible for its E3 ligase activity in ubiquitination or SUMOylation. It interacts with proteins related to mitochondrial fusion and fission, cell survival, and tumor suppressor processes, thus being involved in various cellular processes like mitochondrial dynamics, inter-organelle communication, proliferation, mitophagy, immune response, inflammation, and cell apoptosis [2].

Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype resistant to high-fat diet-induced obesity and metabolic syndrome. Key enzymes for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are modulated in the absence of MUL1, leading to diminished fat storage and heightened fatty acid oxidation [3]. Also, Mul1 deficiency in neurons increases Mfn2 activity, triggering mitochondrial hyperfusion and acting as an antagonist of ER-mitochondria tethering. This leads to increased cytoplasmic Ca2+ load, activating calcineurin and inducing mitochondrial fragmentation and mitophagy [4,5]. In ovarian cancer cells, knockout of the MUL1 gene significantly increased apoptosis and enhanced the sensitivity to cisplatin [1].

In conclusion, Mul1 plays a crucial role in maintaining mitochondrial function, regulating energy metabolism, and influencing cell survival and apoptosis. Gene knockout mouse models have revealed its significance in obesity-related metabolic diseases, neurodegenerative diseases, and ovarian cancer. Understanding Mul1 can potentially provide new therapeutic targets for these diseases.