MYC Suppresses Mitochondrial Function in Hepatocellular Carcinoma through NRF1-Driven Receptor-Mediated Mitophagy

MYC is a canonical driver of mitochondrial biogenesis, yet its role in mitochondrial homeostasis in cancer remains incompletely understood. Here we show that MYC paradoxically suppresses mitochondrial function in hepatocellular carcinoma (HCC) through elevated receptor-mediated mitophagy. Pan-cancer TCGA analysis revealed that MYC activity exhibited discordant nuclear and mtDNA-encoded mitochondrial gene expression, particularly in liver cancer. Using genetically defined murine HCC models, we demonstrate that MYC, but not b-catenin (CTNNB1), drives mitochondrial fragmentation and turnover through a MYC-NRF1-FUNDC1/PGAM5/DNM1L (DRP1) transcriptional axis. Genetic or pharmacologic inhibition of this axis reduced mitophagy and restored oxidative phosphorylation in tumors while extending survival of tumor-bearing mice. Tumors expressing yeast NDI1, which bypasses Complex I to promote electron transport, restored OXPHOS and reduced tumor burden independent of mitophagy. Our data demonstrate that suppression of mitochondrial OXPHOS unexpectedly supports HCC tumor growth and implicates mitochondrial quality control as a novel therapeutic vulnerability in patients with MYC-amplified HCC.