Complex I drives glutamine-dependent TCA cycle to support viability of MYC high breast cancer cells.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal research with no human clinical data
PubMed 42397738 · doi:10.1016/j.celrep.2026.117629
What was done
Metabolic carbon tracing and biochemical assays were conducted in breast cancer cell lines to evaluate how MYC overexpression alters tricarboxylic acid (TCA) cycle fuel reliance. Researchers also tested the antitumor efficacy of NAD+-depleting mitochondrial complex I inhibitors alone and in combination with glutaminolysis inhibitors in vitro and in MYC-high mouse tumor models.
What was found
Metabolic carbon tracing demonstrated that MYC shifts the primary TCA cycle carbon source from glucose to glutamine, sustained by complex I-mediated NADH oxidation to regenerate NAD+. Inhibiting complex I caused MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYC-high tumors, combined inhibition of complex I and glutaminolysis produced persistent suppression of tumor growth. The abstract reports no numerical values or statistical effect sizes.
Why it matters
This study identifies a metabolic dependency in MYC-driven breast cancers, highlighting dual inhibition of mitochondrial complex I and glutaminolysis as a potential synthetic-lethal therapeutic approach.
Limits
The study is limited to preclinical cell culture and mouse models, meaning human clinical efficacy and safety remain unproven. The abstract does not state sample sizes, specific drug names, dosages, quantitative tumor growth metrics, or toxicity data.
Cited by
- contradicts Every known cancer genetic risk factor mutation impairs the efficiency of mitochondrial oxidative phosphorylation.