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

ABSTRACT: In many cancers, stably elevated MYC levels drive persistent and concerted activation of cell growth promoting anabolic programs and cell cycle in ways distinct from normal cells. Therefore, synthetic-lethal targeting of MYC-reprogrammed pathways offers selective strategies against MYChigh tumors. This study identifies enhanced mitochondrial respiration as a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH. Metabolic carbon tracing analysis reveals that MYC shifts TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, persistent inhibition of tumor growth is achieved through combined inhibition of complex I and glutaminolysis. Altogether, the high respiration rate observed in MYChigh cells supports a glutamine carbon-enriched TCA cycle rendering MYChigh tumors selectively vulnerable to inhibitors of mitochondrial respiration and glutaminolysis. This deposition specifically contains the RNA-sequencing data generated from the breast cancer cell lines described in the study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE331349 | GEO | 2026/05/19

REPOSITORIES: GEO

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