br Lactate metabolism L Lactate is an intermediate
Lactate metabolism L-Lactate is an intermediate metabolite in glucose metabolism. Glucose can be broken down to pyruvate, and pyruvate can be either further oxidized to acetyl-CoA and enter the TCA cycle, or reduced to L-lactate by lactate dehydrogenase (LDH). In turn, LDH can oxidize L-lactate to pyruvate and enter the TCA cycle. L-Lactate can be efficiently oxidized by 10-Hydroxycamptothecin cells, serving as preferred fuel for brain metabolism , . A recent study showed that inhibition of LDH could have a similar protective effect to that observed through inhibition of glycolysis . According to this study, inhibition of LDH would reduce astrocytic lactate-derived pyruvate supply into mitochondria. The authors suggested that reducing pyruvate metabolic flux reduces chemically induced seizures in experimental mouse models. This is consistent with the aforementioned hypothesis that reduction in glycolytic flux rather than increase in ketone body utilization has a protective effect on epileptic seizures , . In addition, the study by Sada et al. opened the door to treat epileptic seizures by targeting metabolic pathways using potent inhibitors of LDH . This strategy appears to be very appealing, as it could constitute a way to mimic the ketogenic diet while avoiding the diet and its undesired side effects. However, unlike the ketogenic diet, inhibition of LDH does not supply an alternative source of energy, thus questioning its feasibility as a long-term treatment, although it might still be used to enhance the effects of the ketogenic diet or diets with low glycemic index . Nonetheless, preventing the usage of lactate as a neuronal energy fuel has a dramatic effect on epileptic seizures. This highlights the strong connection between metabolic flow and neuronal excitability beyond energy supply. In this regard, the fate of L-lactate in neurons has been examined in detail to understand its contribution to energy metabolism and neuronal electrical activity. Full oxidation of L-lactate in the brain requires the use of the Malate-Asparte Shuttle (MAS), in charge of importing cytosolic NADH into mitochondria for oxidation at the electron transport chain . Using a genetic approach with select ablation of components of the MAS, L-lactate was determined to be a key energy fuel for neurons to recover after an excitotoxic challenge . In addition, impairment of L-lactate utilization due to interference with MAS function also resulted in an increase in oxidative stress, which could be due to the reduction in mitochondrial NADH formation and subsequent maintenance of redox homeostasis through the glutathione system . In light of these findings, it could be speculated that the dependence of neurons on L-lactate to deal with a high workload is due to the fact that glucose might be diverted away from mitochondrial metabolism to feed the pentose phosphate pathway. Therefore, the role of lactate as purely an energy substrate, would allow glucose to feed the pentose phosphate pathways and generate NADPH, necessary to maintain redox homeostasis pathways and prevent oxidative stress through the thioredoxin and glutathione systems , as well as provide ribose for nucleotide synthesis, thus counteracting nucleotide depletion due to excessive glutamate-triggered cell death and subsequent poly-ADP ribosylation . In support of the role of L-lactate as predominant energy fuel in the brain that contributes to fine-tune neuronal firing rates, another study recently highlighted the importance of L-lactate-derived ATP to support neuronal function . Furthermore, it was shown that part of L-lactate-derived ATP can also be secreted to act as a signaling molecule that activates P2Y purinergic receptors, triggering the pro-survival PI3-kinase signaling pathway and leading to eventual opening of KATP channels . Altogether, and in light of the discussed evidence, L-lactate appears to be an essential metabolite to supply energy and modulate neuronal excitability through multiple pathways . In addition, L-lactate may also exert its effects through extracellular pathways that will be briefly discussed below.