Abstract 5396: NDUFA4L2 inhibits oxidative phosphorylation to drive primary tumor escape

Metastasis causes most cancer deaths and cancer cells require metabolic adaptation to spread to new tissues. However, the metabolic requirements of epithelial to mesenchymal transition (EMT) for primary tumor escape are uncertain. Analyses of Renal Cell Carcinoma (RCC) tumors found mesenchymal cancer cells had elevated expression of the mitochondrial electron transport inhibitor NDUFA4L2 and were glycolytic. NDUFA4L2 suppressed oxidative phosphorylation and was essential for EMT and spontaneous metastasis in RCC models. Mechanistically, NDUFA4L2 caused a build-up of TCA cycle intermediates and modified chromatin accessibility of EMT-related loci. This appeared due to altered mitochondrial oxidative phosphorylation, as increased electron transport complex 1 inhibited EMT and Fumarate Hydratase deficiency drove metastasis. Impaired oxidative phosphorylation thus drives EMT, which is essential for primary tumor escape and metastasis. Citation Format: Emily Nicole Arner, Erin Q. Jennings, Daniel Crooks, Christopher J. Ricketts, Matthew A. Cottam, Kimryn Rathmell, Jeffrey C. Rathmell. NDUFA4L2 inhibits oxidative phosphorylation to drive primary tumor escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5396.