Article

Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells

Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA, USA.
Pigment Cell & Melanoma Research (Impact Factor: 5.64). 02/2012; 25(3):375-83. DOI: 10.1111/j.1755-148X.2012.00989.x
Source: PubMed

ABSTRACT 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.

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    • "The acetyl CoA is then used as a precursor for lipogenesis to maintain cell growth. This process occurs under ischemic conditions in the heart (Comte et al. 2002) and liver (Des Rosiers et al. 1995) and also occurs in hypoxic cancer cells (Filipp et al. 2012; Mullen et al. 2012). Therefore, it is highly possible that this process occurs in blood cells following death. "
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    • "Therefore, the re-programming of mitochondrial citrate metabolism is a central aspect of the PI3K/Akt activity [130]. It has been demonstrated that cells under conditions of hypoxia with defective mitochondria primarily utilise glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate by isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) [131] [132]. There is evidence to support the hypothesis that RC may be triggered by deficient pyruvate oxidation in the mitochondria and the subsequent reduction in citrate levels. "
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