Mitochondrial DNA Alterations Underlie an Irreversible Shift to Aerobic Glycolysis in Fumarate Hydratase-deficient Renal Cancer

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is central to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by bi-allelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed of the mitochondrial in tumors from HLRCC patients. Biochemical and transcriptomics analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of expression of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer. Transcriptome profiling was performed on RNA from five primary HLRCC tumors and paired normal tissue, as well as from 16 metastatic tumors, for a total of 26 samples. Expression levels of tricarboxylic acid (TCA) cycle enzymes and both nuclear and mitochondrial genes encoding Complexes I- V components were evaluated for differential expression among the normal, primary, and metastatic samples. Results were confirmed with qPCR.