Lactate in the brain: an update on its relevance to brain energy, neurons, glia and panic disorder

Abstract

Abstract:Lactate is considered an important metabolite in the human body, but there has been considerable debate about its roles in brain function. Research in recent years has suggested that lactate from astrocytes may be crucial for supporting axonal function, especially during times of high metabolic demands or hypoglycemia. The astrocyte-neuron lactate transfer shuttle system serves a protective function to ensure a supply of substrates for brain metabolism, and oligodendrocytes appear to also influence availability of lactate. There is increasing evidence for lactate acting as a signaling molecule in the brain to link metabolism, substrate availability, blood flow and neuronal activity. This review will attempt to connect evidence to the relationship lactate has to panic disorder (PD), which suggests that its transporters, receptors or metabolism warrant investigation as potential therapeutic targets in PD.

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

“…Our data and findings of Lenting and co‐workers indicate that in IDH1 mut gliomas lactate is actively imported into the cell in contrast to the Warburg effect. This results in metabolic changes specific to IDH1 mut gliomas and tailored to the tumor microenvironment in which large amounts of both glutamate and lactate are present . In both IDH1 mut glioma tissues and glioma cell culture models with the IDH1 mutation, a decrease in both glutamate and lactate levels is reported .…”

“…This results in metabolic changes specific to IDH1 mut gliomas and tailored to the tumor microenvironment in which large amounts of both glutamate and lactate are present. 20,21 In both IDH1 mut glioma tissues and glioma cell culture models with the IDH1 mutation, a decrease in both glutamate and lactate levels is reported. 22,23 These observations confirm our data and support an increased conversion of both lactate and glutamate into glioma cells with the IDH1 mut.…”

Mechanisms for the maintenance and regulation of axonal energy supply

“…While these studies certainly highlight the importance of lactate uptake in brain function, additional work is needed to parse the directionality of lactate transport and underlying mechanisms of neuroprotection. Considering the widespread controversy over the existence of the ANLS (Chih et al, ; Chih & Roberts, ; Dienel, ; Dienel & Cruz, ; Ferguson et al, ; Riske et al, ; Yellen, ), it is worthwhile to consider the underlying assumptions and open questions regarding the hypothesized model in which axons rely on oligodendrocyte‐derived lactate. Specifically, the current model rests on three primary assumptions: (a) post‐myelination oligodendrocytes favor aerobic glycolysis, leading to a high intracellular lactate concentration relative to the periaxonal space; (b) myelinated axons exhibit a low intracellular lactate concentration relative to the periaxonal space; and (c) myelinated axons metabolize oligodendrocyte‐derived lactate.…”

“…In order for lactate to be imported into myelinated axons, axonal lactate concentration must be low relative to the periaxonal space. As discussed previously, whether neurons primarily utilize oxphos or glycolysis and under what activation states is a highly controversial matter (Chih et al, ; Chih & Roberts, ; Dienel, ; Dienel & Cruz, ; Ferguson et al, ; Riske et al, ; Yellen, ). Considering the heterogenous findings between intracellular compartments and resting versus stimulated nerve cells, it seems imperative to interpret results only within the context measured.…”

“…In addition, we discuss the emerging hypothesis that oligodendrocytes support axonal energy metabolism, review the evidence surrounding this hypothesis, and highlight questions that remain to be answered. For additional insights and alternative perspectives of neuronal energy metabolism, we refer readers to the following articles (Ashrafi & Ryan, ; Attwell & Laughlin, ; Chih & Roberts, ; Dienel, ; Harris & Attwell, ; Magistretti & Allaman, ; Pathak et al, ; Pellerin, Bouzier‐Sore, Aubert, Serres, & Merle, ; Riske, Thomas, Baker, & Dursun, ; Sheng, ; Yellen, ).…”