Open AccessMitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase–deficient renal cancer
Author(s) -
Daniel R. Crooks,
Nunziata Maio,
Martin Lang,
Christopher J. Ricketts,
Cathy D. Vocke,
Sandeep Gurram,
Sevilay Turan,
Yunyoung 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. Malayeri,
María J. Merino,
Youfeng Yang,
Jordan L. Meier,
Mark W. Ball,
Tracey A. Rouault,
Ramaprasad Srinivasan,
W. Marston Linehan
Publication year - 2021
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.abc4436
Subject(s) - fumarase , mitochondrial dna , biology , anaerobic glycolysis , mitochondrial respiratory chain , warburg effect , respiratory chain , cancer research , glycolysis , cancer , mitochondrion , microbiology and biotechnology , biochemistry , cancer cell , gene , genetics , enzyme
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.