Light shed on a non-canonical TCA cycle: cell state regulation beyond mitochondrial energy production

A recent publication in Nature by Arnold et al. reports on the discovery of a non-canonical tricarboxylic acid (TCA) cycle in which acetyl-CoA produced from mitochondrially derived citrate by ACLY regenerates oxaloacetate in the cytoplasm. 1 Oxaloacetate is converted through a two-direction reaction to malate, which is uptaken by the mitochondrial citrate/malate transporter SLC25A1 in the mitochondria, where it fuels oxaloacetate and citrate production (Fig. 1a ). Fig. 1 Schematic representation of the two modules of the TCA cycle. a non-canonical TCA cycle in proliferating cells, where citrate is exported to the cytoplasm and cleaved by ACLY to produce acetyl-CoA and regenerate oxaloacetate, which yields malate that is transported back to mitochondria. b canonical TCA cycle from citrate to malate in mitochondria, mainly present in differentiated cells. Tracing of M+2 citrate derived from [U- 13 C]glucose to M+2 malate, when metabolized by aconitase (ACO) in the canonical TCA cycle ( b ), or to unlabeled malate, when metabolized by ACLY in the cytoplasm ( a ), is shown. Created with BioRender.com Full size image