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. Malayeri; Maria J. Merino; Youfeng Yang; Jordan L. Meier; Mark W. Ball; Tracey A. Rouault; Ramaprasad Srinivasan; W. Marston Linehan

doi:10.1126/SCISIGNAL.ABC4436

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

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32 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 language	English
Article number	eabc4436
Journal	Science Signaling
Volume	14
Issue number	664
DOIs	https://doi.org/10.1126/SCISIGNAL.ABC4436
State	Published - Jan 2021

Bibliographical note

Funding 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.

Publisher Copyright:
Copyright © 2021 The Authors.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1126/SCISIGNAL.ABC4436

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Crooks, D. R., Maio, N., Lang, M., Ricketts, C. J., Vocke, C. D., Gurram, S., Turan, S., Kim, Y. Y., Cawthon, G. M., Sohelian, F., De Val, N., Pfeiffer, R. M., Jailwala, P., Tandon, M., Tran, B., Fan, T. W. M., Lane, A. N., Ried, T., Wangsa, D., ... Linehan, W. M. (2021). Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer. Science Signaling, 14(664), [eabc4436]. https://doi.org/10.1126/SCISIGNAL.ABC4436

@article{3b77a412174143a6919926613aa32e97,

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

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.",

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

note = "Funding 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. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors.",

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doi = "10.1126/SCISIGNAL.ABC4436",

language = "English",

volume = "14",

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Crooks, DR, Maio, N, Lang, M, Ricketts, CJ, Vocke, CD, Gurram, S, Turan, S, Kim, YY, Cawthon, GM, Sohelian, F, De Val, N, Pfeiffer, RM, Jailwala, P, Tandon, M, Tran, B, Fan, TWM , Lane, AN, Ried, T, Wangsa, D, Malayeri, AA, Merino, MJ, Yang, Y, Meier, JL, Ball, MW, Rouault, TA, Srinivasan, R & Linehan, WM 2021, 'Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer', Science Signaling, vol. 14, no. 664, eabc4436. https://doi.org/10.1126/SCISIGNAL.ABC4436

TY - JOUR

T1 - Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer

AU - Crooks, Daniel R.

AU - Maio, Nunziata

AU - Lang, Martin

AU - Ricketts, Christopher J.

AU - Vocke, Cathy D.

AU - Gurram, Sandeep

AU - Turan, Sevilay

AU - Kim, Yun Young

AU - Cawthon, G. Mariah

AU - Sohelian, Ferri

AU - De Val, Natalia

AU - Pfeiffer, Ruth M.

AU - Jailwala, Parthav

AU - Tandon, Mayank

AU - Tran, Bao

AU - Fan, Teresa W.M.

AU - Lane, Andrew N.

AU - Ried, Thomas

AU - Wangsa, Darawalee

AU - Malayeri, Ashkan A.

AU - Merino, Maria J.

AU - Yang, Youfeng

AU - Meier, Jordan L.

AU - Ball, Mark W.

AU - Rouault, Tracey A.

AU - Srinivasan, Ramaprasad

AU - Linehan, W. Marston

N1 - Funding 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. Publisher Copyright: Copyright © 2021 The Authors.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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UN SDGs

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