Neuronal Energy Substrates are the various molecules the brain and its constituent cells, including neurons and glia, utilize to generate adenosine triphosphate (ATP) for cellular maintenance and signaling. While glucose is the primary and obligate substrate, the brain possesses the metabolic flexibility to efficiently utilize alternative fuels, most notably ketone bodies and lactate, under specific physiological conditions. The availability and diversity of these substrates are crucial for sustained cognitive function and neuroprotection.
Origin
This term is rooted in neurophysiology and metabolic biochemistry, specifically the study of cerebral metabolism and the brain’s high, non-stop energy demands. The recognition of substrates beyond glucose gained clinical significance through research into fasting, ketogenic interventions, and conditions where glucose utilization is impaired. Understanding the full range of energy options informs therapeutic strategies for cognitive enhancement and neurological resilience.
Mechanism
Glucose is transported across the blood-brain barrier via GLUT1 transporters, entering the glycolytic pathway. Lactate, produced by astrocytes from glucose or transported from the periphery, can be utilized by neurons via the astrocyte-neuron lactate shuttle. Ketone bodies, primarily beta-hydroxybutyrate, enter the brain via monocarboxylate transporters and are converted to acetyl-CoA for mitochondrial oxidation. This substrate diversity ensures continuous, high-fidelity energy supply, particularly during metabolic stress.
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