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

被引：66

作者：

Crooks, Daniel R. ^{[1
]}

Maio, Nunziata ^{[2
]}

Lang, Martin ^{[1
]}

Ricketts, Christopher J. ^{[1
]}

Vocke, Cathy D. ^{[1
]}

Gurram, Sandeep ^{[1
]}

Turan, Sevilay ^{[3
]}

Kim, Yun-Young ^{[1
]}

Cawthon, G. Mariah ^{[1
]}

Sohelian, Ferri ^{[4
]}

De Val, Natalia ^{[4
]}

Pfeiffer, Ruth M. ^{[5
]}

Jailwala, Parthav ^{[6
,7
]}

Tandon, Mayank ^{[6
,7
]}

Tran, Bao ^{[3
]}

Fan, Teresa W-M ^{[8
,9
]}

Lane, Andrew N. ^{[8
,9
]}

Ried, Thomas ^{[10
]}

Wangsa, Darawalee ^{[10
]}

Malayeri, Ashkan A. ^{[11
]}

Merino, Maria J. ^{[12
]}

Yang, Youfeng ^{[1
]}

Meier, Jordan L. ^{[13
]}

Ball, Mark W. ^{[1
]}

Rouault, Tracey A. ^{[2
]}

Srinivasan, Ramaprasad ^{[1
]}

Linehan, W. Marston ^{[1
]}

机构：

[1] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[2] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Med Branch, Bethesda, MD 20892 USA

[3] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Sequencing Facil, Frederick, MD 21701 USA

[4] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Electron Microscopy Lab, Frederick, MD 21702 USA

[5] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA

[6] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, CCR Collaborat Bioinformat Resource CCBR, Frederick, MD 21702 USA

[7] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Computat Sci, Frederick, MD 21702 USA

[8] Univ Kentucky, Ctr Environm & Syst Biochem, Dept Toxicol & Canc Biol, Lexington, KY 40536 USA

[9] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA

[10] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[11] NIH, Radiol & Imaging Sci, Clin Ctr, Bethesda, MD 20892 USA

[12] NCI, Genitourinary Pathol Sect, Lab Pathol, Bethesda, MD 20892 USA

[13] NCI, Epigenet & Metab Sect, Chem Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA

来源：

SCIENCE SIGNALING | 2021年 / 14卷 / 664期

关键词：

POSITRON-EMISSION-TOMOGRAPHY; TRANSCRIPTION FACTOR; HEREDITARY LEIOMYOMATOSIS; REDUCTIVE CARBOXYLATION; POLYMERASE-GAMMA; CELL CARCINOMA; METABOLISM; MUTATIONS; SUCCINATION; COMPLEXES;

D O I：

10.1126/scisignal.abc4436

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：18

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