Cancer cells overexpressing uncoupling protein 2 (UCP2), a mitochondrial carrier, shift their metabolism from glycolysis toward oxidative phosphorylation and become less proliferative and poorly tumorigenic. Indeed, immunodeficient mice implanted subcutaneously with melanoma B16F10 cells (top) developed bigger tumors than UCP2 overexpressing B16F10 cells (bottom). Our results further demonstrate that, by controlling mitochondrial substrate routing, UCP2 drives a feed-forward loop from mitochondria to AMPK and HIF, with direct impact on the transformed phenotype of cancer cells. For details, see article by Esteves and colleagues on page 3971.