Publication Date:
2011-11-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262117/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262117/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 5T32GM083831/GM/NIGMS NIH HHS/ -- DK078933/DK/NIDDK NIH HHS/ -- K01 DK078933/DK/NIDDK NIH HHS/ -- K01 DK078933-03/DK/NIDDK NIH HHS/ -- K08 DK072565/DK/NIDDK NIH HHS/ -- K08 DK072565-06/DK/NIDDK NIH HHS/ -- K08DK072565/DK/NIDDK NIH HHS/ -- P41 RR002584/RR/NCRR NIH HHS/ -- P41 RR002584-22/RR/NCRR NIH HHS/ -- R01 CA123067/CA/NCI NIH HHS/ -- R01 CA123067-05/CA/NCI NIH HHS/ -- R01 CA157996/CA/NCI NIH HHS/ -- R01 CA157996-01/CA/NCI NIH HHS/ -- R01CA123067/CA/NCI NIH HHS/ -- R01CA157996/CA/NCI NIH HHS/ -- RR02584/RR/NCRR NIH HHS/ -- T32 CA009560/CA/NCI NIH HHS/ -- T32 CA009560-20/CA/NCI NIH HHS/ -- T32 GM008061/GM/NIGMS NIH HHS/ -- T32 GM008061-30/GM/NIGMS NIH HHS/ -- T32 GM083831/GM/NIGMS NIH HHS/ -- T32 GM083831-04/GM/NIGMS NIH HHS/ -- T32CA009560/CA/NCI NIH HHS/ -- T32GM008061/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 20;481(7381):385-8. doi: 10.1038/nature10642.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, University of Texas - Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22101431" target="_blank"〉PubMed〈/a〉
Keywords:
Acetyl Coenzyme A/metabolism
;
Animals
;
Carcinoma, Renal Cell/genetics/metabolism/pathology
;
Cell Hypoxia
;
Cell Line, Tumor
;
Citric Acid/metabolism
;
Electron Transport
;
Electron Transport Complex I/metabolism
;
Electron Transport Complex III/metabolism
;
Fumarate Hydratase/genetics/metabolism
;
Glucose/metabolism
;
Glutamine/metabolism
;
Humans
;
Isocitrate Dehydrogenase/metabolism
;
Kidney Neoplasms/genetics/metabolism/pathology
;
Mice
;
Mitochondria/*metabolism/*pathology
;
NADP/metabolism
;
Neoplasms/*metabolism/*pathology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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