Abstract
Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.
Highlights
Published: 18 June 2021Brain function is dependent on the oxidative metabolism of glucose
Since the antioxidative capacity of neurons is not sufficient given their high rate of oxidative metabolism, astrocytes support neurons by providing GSH, taking advantage of the high phosphate pathway (PPP) flux that is associated with their high glycolytic activity (Figure 2) [3,4,5]
We found that nitric oxide (NO) released from microglia activated astroglial PPP flux through the Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1)/nuclear factor erythroid 2 p45 subunit-related factor 2 (Nrf2) system
Summary
Brain function is dependent on the oxidative metabolism of glucose. a human adult brain weighing approximately 2% (1400 g) of the body weight (70 kg) is responsible for 25% of the total glucose consumption of the whole body [1,2]. Most glucose is oxidized by oxygen to generate carbon dioxide (CO2 ) and adenosine triphosphate (ATP) This high rate of oxidative metabolism of glucose cannot be replaced by any other energy substrates under normal physiological conditions [3,4,5]. For example, the elimination of ROSs during reperfusion therapy by either pharmacological thrombolysis or a mechanical thrombectomy is an essential therapeutic strategy, since damaged mitochondria during ischemia serve as a potential source of massive ROS production, especially after reperfusion. Astrocytes produce huge amounts of lactate even under a sufficient supply of oxygen (aerobic glycolysis) Their high glucose consumption and high glycolytic activity leads to lactate production, and lactate, in turn, is transferred to neurons to serve as a tricarboxylic acid (TCA) cycle substrate instead of glucose (astrocyte–neuron lactate shuttle model) [25,26]. We discuss fatty acid metabolism in peroxisomes where very long chain fatty acids are metabolized
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