MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.

Mitochondrial metabolism plays a crucial role in cancer progression and is associated with effective channeling of electrons through Complex I. The ability to adapt this electron flow as per cellular demands is critical for energy homeostasis. Our observations suggest that proliferating cells regulate the electron entry point through alterations in the levels of Methylation-Controlled J-protein (MCJ). Elevated MCJ levels were found to promote aggressive proliferative and migratory phenotypes, leading to increased primary tumor burden. The phenotype was attributed to MCJ-mediated regulation of mitochondrial bioenergetic plasticity, enabling a preferential rerouting of electron flux through succinate dehydrogenase complex (Complex II). Consequently, cells exhibited suppressed glycolysis and a metabolic shift toward lipid-fueled mitochondrial respiration, marked by increased lipid accumulation and its oxidation. Despite Complex I uncoupling, these cells maintained better respiratory output and preserved NADH levels to support an increased redox potential. These findings decouple the reliance on Complex I for effective mitochondrial respiration and underscore the significance of Complex II-driven metabolism in tumor growth, an important consideration for development of future therapeutics, particularly when current strategies predominantly target Complex I-dependent respiration.