Glycerol-3-Phosphate Shuttle Is a Backup System Securing Metabolic Flexibility in Neurons

Abstract

Electrical activity in neurons is highly energy demanding and accompanied by rises in cytosolic Ca 21 . Cytosolic Ca 21 , in turn, secures energy supply by pushing mitochondrial metabolism either through augmented NADH (nicotinamide adenine dinucleotide) transfer into mitochondria via the malate-aspartate shuttle (MAS) or via direct activation of dehydrogenases of the TCA cycle after passing into the matrix through the mitochondrial Ca 21 uniporter (MCU). Another Ca 21 -sensitive booster of mitochondrial ATP synthesis is the glycerol-3-phosphate shuttle (G3PS), whose role in neuronal energy supply has remained elusive. Essential components of G3PS are expressed in hippocampal neurons. Single neuron metabolic measurements in primary hippocampal cultures derived from rat pups of either sex reveal only moderate, if any, constitutive activity of G3PS. However, during electrical activity neurons fully rely on G3PS when MAS and MCU are unavailable. Under these conditions, G3PS is required for appropriate action potential firing. Accordingly, G3PS safeguards metabolic flexibility of neurons to cope with energy demands of electrical signaling.

A species difference in glycerol-3-phosphate metabolism reveals metabolic adaptations in hares

“…Suspecting that higher G3P shuttle capacity could be linked to increased thermogenesis in LT cells, we measured changes in intramitochondrial temperature using Mito Thermo Yellow (MTY). MTY is a thermosensitive fluorescent dye which accumulates inside the mitochondrial matrix and changes fluorescence as an inverse function of temperature i.e., higher MTY signal indicates lower mitochondrial temperature (25)(26)(27). After inhibition of Complex I by rotenone the drop in mitochondrial temperature (DT°) was 35% lower in the LT cells (Figure 2C).…”

“…Synthesized from carbohydrates, amino acids, as well as from triglycerides, G3P can be metabolized in the mitochondria by GPD2 to generate ATP and heat, or used for synthesis of glycerolipids, or triglycerides. Increased G3P availability is therefore often seen as a hallmark of improved metabolic flexibility (25). This led us to hypothesize that mountain hare cells might have sacrificed growth in exchange for enhanced metabolic adaptability to external stressors such as cold.…”

The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner

“…The glycerol 3-phosphate shuttle is a system which transports reducing equivalents from reduced nicotinamide adenine dinucleotide (NADH) into the mitochondria by interconverting dihydroxyacetone phosphate and glycerol 3-phosphate, in order to regenerate cytosolic NAD+ [ 46 ]. This system is important in neurons for metabolic flexibility and is activated when energy demands increase, such as during long-term potentiation [ 47 , 48 ]. Nudifloramide was also in the top 15 metabolites by VIP score in the PLS-DA analysis of all four study groups, and levels in the brain were increased by obesity in both sexes.…”

Mitochondrial calcium uniporter deficiency in dentate granule cells remodels neuronal metabolism and impairs reversal learning

“…In addition, increased complex‐II activity could also favor the oxidation of FADH 2 resulting from the shuttling of glycolytic reducing equivalents to mitochondria via the G3P shuttle. This mitochondrial shuttle system has been identified as a safety mechanism that operates in conditions when both MCU and malate–aspartate shuttle activities are acutely inhibited (Dhoundiyal et al, 2022). Further research is necessary to elucidate whether MAS activity in MCU‐deficient neurons could be maximized during periods of intense activity, thus enabling the G3P shuttle to contribute to mitochondrial respiration; or whether the components of the G3P shuttle could become sufficiently up‐regulated that they could compete with the MAS for glycolytic NADH.…”