RESUMEN

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.

Asunto(s)

Carcinoma de Células Renales/genética , Ciclo del Ácido Cítrico , Daño del ADN , ADN Mitocondrial/metabolismo , Fumarato Hidratasa/genética , Neoplasias Renales/genética , Leiomiomatosis/enzimología , Síndromes Neoplásicos Hereditarios/enzimología , Neoplasias Cutáneas/enzimología , Neoplasias Uterinas/enzimología , Adulto , Anciano , Carcinoma de Células Renales/etiología , Carcinoma de Células Renales/metabolismo , Reparación del ADN , Replicación del ADN , Femenino , Fumarato Hidratasa/deficiencia , Perfilación de la Expresión Génica , Humanos , Neoplasias Renales/etiología , Neoplasias Renales/metabolismo , Leiomiomatosis/complicaciones , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación , Síndromes Neoplásicos Hereditarios/complicaciones , Neoplasias Cutáneas/complicaciones , Neoplasias Uterinas/complicaciones , Adulto Joven