Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

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 -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.