Reductive carboxylation supports growth in tumour cells with defective mitochondria

Andrew R. Mullen, William W. Wheaton, Eunsook S. Jin, Pei Hsuan Chen, Lucas B. Sullivan, Tzuling Cheng, Youfeng Yang, W. Marston Linehan, Navdeep S. Chandel, Ralph J. Deberardinis

Research output: Contribution to journalArticle

587 Citations (Scopus)

Abstract

Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose-and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP +/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.

Original languageEnglish (US)
Pages (from-to)385-388
Number of pages4
JournalNature
Volume481
Issue number7381
DOIs
StatePublished - Jan 19 2012

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Mitochondria
Glutamine
Citric Acid Cycle
Growth
Neoplasms
Citric Acid
Acetyl Coenzyme A
Electron Transport
NADP
Mutation
Carbon
Fumarate Hydratase
Lipids
Isocitrate Dehydrogenase
Electron Transport Complex III
Renal Cell Carcinoma
Protein Isoforms
Carcinogenesis
Pharmacology
Glucose

ASJC Scopus subject areas

  • General

Cite this

Reductive carboxylation supports growth in tumour cells with defective mitochondria. / Mullen, Andrew R.; Wheaton, William W.; Jin, Eunsook S.; Chen, Pei Hsuan; Sullivan, Lucas B.; Cheng, Tzuling; Yang, Youfeng; Linehan, W. Marston; Chandel, Navdeep S.; Deberardinis, Ralph J.

In: Nature, Vol. 481, No. 7381, 19.01.2012, p. 385-388.

Research output: Contribution to journalArticle

Mullen, AR, Wheaton, WW, Jin, ES, Chen, PH, Sullivan, LB, Cheng, T, Yang, Y, Linehan, WM, Chandel, NS & Deberardinis, RJ 2012, 'Reductive carboxylation supports growth in tumour cells with defective mitochondria', Nature, vol. 481, no. 7381, pp. 385-388. https://doi.org/10.1038/nature10642
Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012 Jan 19;481(7381):385-388. https://doi.org/10.1038/nature10642
Mullen, Andrew R. ; Wheaton, William W. ; Jin, Eunsook S. ; Chen, Pei Hsuan ; Sullivan, Lucas B. ; Cheng, Tzuling ; Yang, Youfeng ; Linehan, W. Marston ; Chandel, Navdeep S. ; Deberardinis, Ralph J. / Reductive carboxylation supports growth in tumour cells with defective mitochondria. In: Nature. 2012 ; Vol. 481, No. 7381. pp. 385-388.
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