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ORIGINAL ARTICLE
Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells
Article first published online: 27 MAR 2012
DOI: 10.1111/j.1755-148X.2012.00989.x
Published 2012. This article is a U.S. Government work and is in the public domain in the USA
Additional Information
How to Cite
Filipp, F. V., Scott, D. A., Ronai, Z. A., Osterman, A. L. and Smith, J. W. (2012), Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell & Melanoma Research, 25: 375–383. doi: 10.1111/j.1755-148X.2012.00989.x
Publication History
- Issue published online: 17 APR 2012
- Article first published online: 27 MAR 2012
- Accepted manuscript online: 23 FEB 2012 03:26PM EST
- PUBLICATION DATA Received 13 December 2011, revised and accepted for publication 20 February 2012, published online 23 February 2012
- Abstract
- Article
- References
- Cited By
Keywords:
- IDH;
- metabolism;
- flux;
- NMR;
- 13C;
- hypoxia;
- reductive carboxylation
Summary
The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in the classic forward direction to provide carbon for biosynthesis and reducing agents for generation of ATP. Our metabolic tracer studies in melanoma cells showed that in hypoxic conditions the TCA cycle is largely disconnected from glycolysis. By studying the TCA branch point metabolites, acetyl CoA and citrate, as well as the metabolic endpoint glutamine and fatty acids, we developed a comprehensive picture of the rewiring of the TCA cycle that occurs in hypoxia. Hypoxic tumor cells maintain proliferation by running the TCA cycle in reverse. The source of carbon for acetyl CoA, citrate, and fatty acids switches from glucose in normoxia to glutamine in hypoxia. This hypoxic flux from glutamine into fatty acids is mediated by reductive carboxylation. This reductive carboxylation is catalyzed by two isocitrate dehydrogenases, IDH1 and IDH2. Their combined action is necessary and sufficient to effect the reverse TCA flux and maintain cellular viability.