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

Daniel R. Crooks, Nunziata Maio, Martin Lang, Christopher J. Ricketts, Cathy D. Vocke, Sandeep Gurram, Sevilay Turan, Yun Young Kim, G. Mariah Cawthon, Ferri Sohelian, Natalia De Val, Ruth M. Pfeiffer, Parthav Jailwala, Mayank Tandon, Bao Tran, Teresa W.M. Fan, Andrew N. Lane, Thomas Ried, Darawalee Wangsa, Ashkan A. MalayeriMaria J. Merino, Youfeng Yang, Jordan L. Meier, Mark W. Ball, Tracey A. Rouault, Ramaprasad Srinivasan, W. Marston Linehan

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereabc4436
JournalScience Signaling
Volume14
Issue number664
DOIs
StatePublished - Jan 2021

Bibliographical note

Publisher Copyright:
Copyright © 2021 The Authors.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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