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. Malayeri

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

Research output: Contribution to journal › Article › peer-review

75 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

Publisher Copyright:
Copyright © 2021 The Authors.

Funding

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.

Funders	Funder number
NCI-CCR
National Institutes of Health (NIH)	HHSN26120080001E
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	ZIAHD001602
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Frederick National Laboratory for Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1126/SCISIGNAL.ABC4436

Cite this

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), Article 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 = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors.",

year = "2021",

month = jan,

doi = "10.1126/SCISIGNAL.ABC4436",

language = "English",

volume = "14",

number = "664",

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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

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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

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.

UR - https://www.scopus.com/pages/publications/85099425039

UR - https://www.scopus.com/pages/publications/85099425039#tab=citedBy

U2 - 10.1126/SCISIGNAL.ABC4436

DO - 10.1126/SCISIGNAL.ABC4436

M3 - Article

C2 - 33402335

AN - SCOPUS:85099425039

SN - 1945-0877

VL - 14

JO - Science Signaling

JF - Science Signaling

IS - 664

M1 - eabc4436

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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Cite this