Figure 5.

Updated working model of citrate metabolism in mouse and human prostate. A) The current working model of prostate metabolism describes a truncated TCA cycle that allows massive citrate secretion into the semen. In this model, glucose and aspartate are both essential for acetyl-CoA and oxaloacetate synthesis to sustain citrate synthesis by citrate synthase. However, metabolomics using mouse prostate tissues and mouse and human prostate organoids showed herein dress a more complex profile in the mouse (B) and human (C) prostate. First, aspartate is not essential for citrate synthesis. Second, citrate, but also downstream intermediates, can be produced using glucose, aspartate, and glutamine as carbon sources. Glutamine was revealed to be a significant nutrient contributing to citrate secretion by both allowing α-ketoglutarate (αΚG) production for synthesis of downstream intermediates and by reductive carboxylation of αΚG. The current study also revealed that aspartate can enter at different entry points of the TCA cycle. In human prostate organoids, aspartate appears to enter the TCA cycle in a way that mimics the malate–aspartate shuttle, providing malate for the synthesis of citrate. Sizes of the arrows indicate the respective contribution of the different nutrients to the TCA cycle and to citrate secretion.