Complex I Drives Glutamine-Dependent TCA Cycle to Support Viability of MYC high Breast Cancer Cells

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Abstract In many cancers, stably elevated MYC levels drive persistent and concerted activation of cell growth promoting anabolic programs and the cell cycle in ways that are distinct from normal cells. Therefore, synthetic-lethal strategies to target MYC reprograming of these pathways may identify new selective anticancer therapies for the treatment of MYC high tumors. Here, we identify enhanced mitochondrial respiration as a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD + through complex I-mediated oxidation of NADH. Metabolic carbon tracing analysis revealed that MYC shifts TCA cycle’s carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD + -depleting complex I inhibitors resulted in MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYC high tumors, persistent inhibition of tumor growth was achieved through combined inhibition of complex I and glutaminolysis. Our results suggest that the high respiration rate observed in MYC high cells supports glutamine carbon-enriched TCA cycle, rendering MYC high tumors selectively vulnerable to inhibitors of mitochondrial respiration and glutaminolysis.

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