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

Research ArticleCancer

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

View ORCID ProfileDaniel R. Crooks¹,*,
View ORCID ProfileNunziata Maio²,*,
View ORCID ProfileMartin Lang¹,
View ORCID ProfileChristopher J. Ricketts¹,
View ORCID ProfileCathy D. Vocke¹,
View ORCID ProfileSandeep Gurram¹,
Sevilay Turan³,
View ORCID ProfileYun-Young Kim¹,
G. Mariah Cawthon¹,
Ferri Sohelian⁴,
View ORCID ProfileNatalia De Val⁴,
View ORCID ProfileRuth M. Pfeiffer⁵,
Parthav Jailwala⁶,⁷,
View ORCID ProfileMayank Tandon⁶,⁷,
Bao Tran³,
View ORCID ProfileTeresa W.-M. Fan⁸,
Andrew N. Lane⁸,
View ORCID ProfileThomas Ried⁹,
Darawalee Wangsa⁹,
Ashkan A. Malayeri¹⁰,
Maria J. Merino¹¹,
Youfeng Yang¹,
View ORCID ProfileJordan L. Meier¹²,
View ORCID ProfileMark W. Ball¹,
View ORCID ProfileTracey A. Rouault²,
View ORCID ProfileRamaprasad Srinivasan¹, and
View ORCID ProfileW. Marston Linehan¹,†

¹Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
²Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
³Sequencing Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA.
⁴Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
⁵Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
⁶CCR Collaborative Bioinformatics Resource (CCBR), Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
⁷Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
⁸Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
⁹Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁰Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
¹¹Genitourinary Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
¹²Epigenetics and Metabolism Section, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

↵†Corresponding author. Email: wml{at}nih.gov

↵* These authors contributed equally to this work.

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Science Signaling 05 Jan 2021:
Vol. 14, Issue 664, eabc4436
DOI: 10.1126/scisignal.abc4436

Daniel R. Crooks

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Nunziata Maio

2Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.

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Martin Lang

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Christopher J. Ricketts

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Cathy D. Vocke

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Sandeep Gurram

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Sevilay Turan

3Sequencing Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA.

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Yun-Young Kim

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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G. Mariah Cawthon

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Ferri Sohelian

4Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

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Natalia De Val

4Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

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Ruth M. Pfeiffer

5Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.

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Parthav Jailwala

6CCR Collaborative Bioinformatics Resource (CCBR), Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

7Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

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Mayank Tandon

6CCR Collaborative Bioinformatics Resource (CCBR), Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

7Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.

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Bao Tran

3Sequencing Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA.

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Teresa W.-M. Fan

8Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.

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ORCID record for Teresa W.-M. Fan

Andrew N. Lane

8Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.

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Thomas Ried

9Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Darawalee Wangsa

9Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Ashkan A. Malayeri

10Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

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Maria J. Merino

11Genitourinary Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.

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Youfeng Yang

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Jordan L. Meier

12Epigenetics and Metabolism Section, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

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ORCID record for Jordan L. Meier

Mark W. Ball

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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Tracey A. Rouault

2Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.

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Ramaprasad Srinivasan

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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W. Marston Linehan

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

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For correspondence: wml@nih.gov

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

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