Cancer Metabolism

Mitochondria provide cells with much more than ATP produced via the electron transport chain (ETC). Cancer cells are no exception. Although many cancer cells rely primarily on aerobic glycolysis for their energy, they still rely on mitochondria to produce precursors for fatty acid synthesis and other biosynthetic processes. How tumor cells with defective mitochondria produce the lipids necessary for proliferation has been unclear. Mullen et al. (2011) uncover new metabolic flexibility in cancer cells. Glutamine can drive citric acid cycle (CAC) reactions in reverse, such that reductive carboxylation yields acetyl-CoA for lipid synthesis. Glutamine-dependent reductive carboxylation hasbeen recognizedas aminor source of citrate inmammalian cells and as the major source of citrate and acetyl-CoA in P. falciparum, a parasite with limited respiration. By tracing the fate of carbons supplied to osteosarcoma cells by C-glucose or C-glutamine, the authors identify reductive carboxylation as the major source of acetyl-CoA in ETC-deficient cancer cells. Although some tumors carry mutations in ETC components, oncogenic mutations are more commonly found in CAC enzymes like fumarate hydratase (FH). To testwhether these typesofmutationsalso favor glutamine-dependent reductive carboxylation, Mullen et al. (2011) examined the metabolism of renal tumor cells lacking FH activity. When cultured without glutamine, these cells stop proliferating. In the presence of glutamine, FH-deficient cells proliferate by employing both oxidative glutamine metabolism (a process well-known for replenishingCAC intermediates that are depleted under normal growth conditions) and reductive carboxylation of glutamine (contributing lipid building blocks). Despite the association between defective mitochondria and oncogenesis, this study highlights the central importance of mitochondria in cancer, even when they aren’t generating ATP. Mullen, A., et al. (2011). Nature 481, 385–358.