Tumour cells with defective mitochondria are found to use glutamine-dependent reductive carboxylation, rather than oxidative metabolism, as the major pathway of citrate and lipid formation. Oxidative metabolism of glucose has long been considered to be the major provider of carbon for lipid synthesis in animal cells. Two papers in this issue of Nature demonstrate that reductive carboxylation of glutamine is an alternative. Metallo et al. show that various normal and cancerous human cell lines proliferating in hypoxic conditions produce the acetyl-coenzyme A required as a precursor for fatty acid synthesis by the reductive metabolism of glutamine-derived α-ketoglutarate through a pathway requiring isocitrate dehydrogenase 1. Mullen et al. show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation as the major pathway of citrate formation. As well as adding a new dimension to our understanding of cell carbohydrate metabolism, this work suggests that there may be potential therapeutic targets along the reductive carboxylation and glutamine catabolic pathways that could prevent hypoxic tumour growth. Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells1,2. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis3. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function4,5,6,7, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.

Reductive carboxylation supports growth in tumour cells with defective mitochondria