In neurons, pyruvate is normally the starting substrate for the TCA cycle as it catabolically converts to acetyl CoA via the action of pyruvate dehydrogenase (Fig. 1E). Conversely, it can be anabolically carboxylated to form oxaloacetate (and then malate), which promotes anaplerosis through reversed TCA cycle activity (Cappel et al., 2019) to compensate for losses of α-ketoglutarate that occur through the release of the neurotransmitters glutamate and GABA (Hassel, 2001). At the co-enzyme level, continuous conversion of acetaldehyde to acetate in mitochondria exhausts mitochondrial NAD+ needed for driving the forward TCA cycle reactions catalysed by isocitrate, α-ketoglutarate and malate dehydrogenases. When this situation is compounded by the uncontrolled production of acetyl-CoA from acetate, the altered balance in acetyl-CoA/CoA may eventually deplete intra-mitochondrial CoA-SH required for the forward α-ketoglutarate dehydrogenase reaction, thus further diminishing the activities of the TCA cycle.
