Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase–deficient renal cancer

Menée à l'aide de lignées cellulaires et d'échantillons tumoraux issus de patients atteints d'un carcinome à cellules rénales, cette étude met en évidence un mécanisme par lequel des altérations de l'ADN mitochondrial favorisent de manière irréversible la glycolyse aérobique dans les cellules cancéreuses présentant une déficience de la fumarate hydratase

Résumé en anglais

Deficiency in the metabolic enzyme fumarate hydratase distinguishes an aggressive and lethal form of kidney cancer called hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Crooks et al. investigated the molecular basis for why HLRCC tumors rapidly grow and metastasize. Deficiency in fumarate hydratase led to the accumulation of the metabolite fumarate, resulting in the modification and inactivation of factors involved in mitochondrial DNA replication and proofreading. Subsequently, mitochondrial DNA mutations increased, leading to loss of mitochondria and a metabolic shift to aerobic glycolysis. Thus, lack of a crucial metabolic enzyme leads to mitochondrial dysfunction and metabolic rewiring that promote tumor progression and metastasis.Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic 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 respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.