Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Abstract

The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca 2? levels, and that this regulation is required to maintain a tight coupling between neuronal activity and mitochondrial respiration and oxidative phosphorylation. At cytosolic Ca 2? fluctuations below the threshold of the mitochondrial calcium uniporter, there is a positive correlation between Ca 2? and MAS activity; however, if cytosolic Ca 2? increases above the threshold, MAS activity is thought to be reduced by an intricate mechanism. The latter forces the neurons to partly rely on anaerobic glycolysis producing lactate that may be metabolized subsequently, by neurons or other cells. In this review, we will discuss the evidence for Ca 2? -mediated regulation of MAS that have been uncovered over the last decade or so, together with the need for further verification, and examine the metabolic ramifications for neurons.

CrossTalk opposing view: lack of evidence supporting an astrocyte‐to‐neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain

“…In our minds, the current literature and the biochemical design of neurons and astrocytes are largely consistent with a situation according to which both neurons and astrocytes contribute to the surge in extracellular lactate during brain activation; either cell type may then consume lactate when available or the lactate may be dispersed and metabolised elsewhere or even leave the brain (Madsen et al 1999;Hertz et al 2014;Satrustegui & Bak, 2015). The cellular location and timing of lactate synthesis and consumption in the brain in health and disease largely remains an open question that deserves to be investigated with an open mind.…”

“…; Hertz et al . ; Satrustegui & Bak, ). The cellular location and timing of lactate synthesis and consumption in the brain in health and disease largely remains an open question that deserves to be investigated with an open mind.…”

Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake

“…However, it remains to be learned whether this correlation is produced by a direct modulation of glycolytic rate by cytosolic calcium (e.g. Singh et al, 2004; Kim et al, 2016; Nicholson-Fish et al, 2016; Hu et al, 2016), by indirect effects due to Ca 2+ uptake by mitochondria (Duchen, 1992; Satrústegui and Bak, 2015), or simply by the ATP burden produced by the demands of Ca 2+ extrusion.…”

Dual action of L-Lactate on the activity of NR2B-containing NMDA receptors: from potentiation to neuroprotection

“… 37 showing that glutamate does not trigger Glucose utilization but rather inhibits Glucose transport and utilization in neurons. In contrast, other studies showed that neuronal depolarization is accompanied by an increase in cytosolic NADH/NAD + ratio that is associated with a reduction of the malate-aspartate shuttle activity through the glycolytic pathway 38 . It was also observed that Glucose utilization is positively correlated with intracellular Ca 2+ signaling whereas L-Lactate utilization is not 24 , 39 .…”