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.
|State||Published - Jan 2021|
Bibliographical noteFunding Information:
This work was supported by the Intramural Research Programs of NCI-CCR and NICHD. This project was funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN26120080001E. Sanger sequencing was conducted at the CCR Genomics Core at the NCI, NIH, Bethesda, MD, USA.
Copyright © 2021 The Authors.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology