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Review
. 2009 Mar 15;69(6):2163-6.
doi: 10.1158/0008-5472.CAN-08-3722. Epub 2009 Mar 3.

Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism

Ismael Samudio  1 , Michael Fiegl, Michael Andreeff
Affiliations
Review

Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism

Ismael Samudio et al. Cancer Res. .

Abstract

The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. Recent evidence suggests that mitochondrial uncoupling-the abrogation of ATP synthesis in response to mitochondrial membrane potential-promotes the Warburg effect in leukemia cells, and may contribute to chemoresistance. Intriguingly, leukemia cells cultured on bone marrow-derived stromal feeder layers are more resistant to chemotherapy, increase the expression of uncoupling protein 2, and decrease the entry of pyruvate into the Krebs cycle-without compromising the consumption of oxygen, suggesting a shift to the oxidation of nonglucose carbon sources to maintain mitochondrial integrity and function. Because fatty acid oxidation has been linked to chemoresistance and mitochondrial uncoupling, it is tempting to speculate that Warburg's observations may indeed be the result of the preferential oxidation of fatty acids by cancer cell mitochondria. Therefore, targeting fatty acid oxidation or anaplerotic pathways that support fatty acid oxidation may provide additional therapeutic tools for the treatment of hematopoietic malignancies.

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Figures

Figure 1
Figure 1. Mitochondrial uncoupling mediates the metabolic shift to aerobic glycolysis in cancer cells
A) Coupled mitochondria (blue) oxidize pyruvate through the Krebs cycle. B) Uncoupled mitochondria (orange) display a metabolic shift to the oxidation of other carbon sources, supported in part by fatty acid and glutamine metabolism that may depend on UCP2 expression. C) Uncoupled mitochondria are more resistant to cytotoxic insults and oppose the activation of the intrinsic apoptotic pathway.
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