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

TL;DR

This paper shows how a protein called MCJ helps cancer cells grow and spread by changing how they use energy from lipids instead of sugars.

Contribution

The study reveals that MCJ promotes tumor growth by rerouting mitochondrial electron flux through Complex II, bypassing Complex I.

Findings

Elevated MCJ levels lead to increased tumor proliferation and migration.

MCJ reroutes electron flux through Complex II, promoting lipid metabolism.

Cells with high MCJ maintain respiratory output despite Complex I uncoupling.

Abstract

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.

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