C19orf12 inhibits mitochondrial function and enhances the antitumor effects of metformin in non-small cell lung cancer

Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is a hallmark of cancer, yet the mechanisms driving aerobic glycolysis are unclear. In this study, we identified chromosome 19 open reading frame 12 (C19orf12), a gene associated with neurodegeneration, as upregulated in non-small cell lung cancer (NSCLC). Elevated C19orf12 expression is associated with poor prognosis and enhanced metastatic potential in NSCLC cells. High C19orf12 levels repress mitochondrial respiration and decrease glucose flux through the tricarboxylic acid cycle. Mechanistically, C19orf12 interacts with and suppresses the biological function of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) and downregulates the expression of mitochondrial electron transport chain (ETC) genes. Moreover, C19orf12 increases NSCLC cell sensitivity to the tumoricidal effects of metformin by synergistically inhibiting mitochondrial respiration. These findings highlight C19orf12 as a regulator of mitochondrial metabolism in NSCLC and suggest that its elevated expression could serve as a biomarker to predict improved responses to metformin therapy.