Magnetic Resonance Research Center and Departments of Radiology and Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
Magnetic Resonance Research Center and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
J Neurochem. 2024 May;168(5):555-591. doi: 10.1111/jnc.15619. Epub 2022 Sep 11.
The ~1:1 stoichiometry between the rates of neuronal glucose oxidation (CMR) and glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) neurotransmitter (NT) cycling between neurons and astrocytes (V) has been firmly established. However, the mechanistic basis for this relationship is not fully understood, and this knowledge is critical for the interpretation of metabolic and brain imaging studies in normal and diseased brain. The pseudo-malate-aspartate shuttle (pseudo-MAS) model established the requirement for glycolytic metabolism in cultured glutamatergic neurons to produce NADH that is shuttled into mitochondria to support conversion of extracellular Gln (i.e., astrocyte-derived Gln in vivo) into vesicular neurotransmitter Glu. The evaluation of this model revealed that it could explain half of the 1:1 stoichiometry and it has limitations. Modifications of the pseudo-MAS model were, therefore, devised to address major knowledge gaps, that is, submitochondrial glutaminase location, identities of mitochondrial carriers for Gln and other model components, alternative mechanisms to transaminate α-ketoglutarate to form Glu and shuttle glutamine-derived ammonia while maintaining mass balance. All modified models had a similar 0.5 to 1.0 predicted mechanistic stoichiometry between V and the rate of glucose oxidation. Based on studies of brain β-hydroxybutyrate oxidation, about half of CMR may be linked to glutamatergic neurotransmission and localized in pre-synaptic structures that use pseudo-MAS type mechanisms for Glu-Gln cycling. In contrast, neuronal compartments that do not participate in transmitter cycling may use the MAS to sustain glucose oxidation. The evaluation of subcellular compartmentation of neuronal glucose metabolism in vivo is a critically important topic for future studies to understand glutamatergic and GABAergic neurotransmission.
神经元葡萄糖氧化（CMR）与神经元和星形胶质细胞（V）之间谷氨酸（Glu）/γ-氨基丁酸（GABA）-谷氨酰胺（Gln）神经递质（NT）循环的速率之间约为 1:1 的化学计量关系已经得到了牢固确立。然而，这种关系的机制基础尚未完全了解，而这一知识对于解释正常和患病大脑中的代谢和脑成像研究至关重要。假苹果酸-天冬氨酸穿梭（pseudo-MAS）模型确立了培养的谷氨酸能神经元中糖酵解代谢的必要性，以产生 NADH，然后将其穿梭进入线粒体，以支持将细胞外 Gln（即体内星形胶质细胞衍生的 Gln）转化为囊泡神经递质 Glu。对该模型的评估表明，它可以解释 1:1 化学计量关系的一半，并且具有局限性。因此，设计了对 pseudo-MAS 模型的修改以解决主要的知识空白，即亚线粒体谷氨酰胺酶的位置、Gln 和其他模型成分的线粒体载体的身份、替代转氨基作用将α-酮戊二酸转化为 Glu 并穿梭谷氨酰胺衍生的氨同时保持质量平衡的机制。所有修改后的模型都具有类似的 0.5 到 1.0 的预测机制化学计量关系，即 V 与葡萄糖氧化速率之间的关系。基于对脑β-羟丁酸氧化的研究，约一半的 CMR 可能与谷氨酸能神经传递有关，并且定位于使用 pseudo-MAS 类型机制进行 Glu-Gln 循环的突触前结构中。相比之下，不参与递质循环的神经元区室可能使用 MAS 来维持葡萄糖氧化。体内神经元葡萄糖代谢的亚细胞区室化的评估是未来研究理解谷氨酸能和 GABA 能神经传递的一个极其重要的课题。
