2 Neuroscience2.5 Neurochemistry and neurophysiology
2.5.1.1 Brain energy metabolism
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Written by Resident Doctor Committee · Published
New in the 2027 syllabus
The College added this topic for exams from January 2027.
Why the brain needs a steady energy supply
Adenosine triphosphate (ATP) is the molecule cells use as ready energy for work. The brain needs a constant supply to maintain ion gradients, recycle neurotransmitters and build new molecules (biosynthesis). It holds little stored fuel, so any break in oxygen or glucose delivery quickly becomes dangerous.
From glucose to ATP
Glucose crosses the blood-brain barrier through glucose transporter 1 (GLUT1). Glucose transporter 3 (GLUT3) helps neurones take it up.
Glycolysis breaks glucose down to pyruvate in the cytosol (the fluid inside the cell).
Pyruvate dehydrogenase turns pyruvate into acetyl coenzyme A (acetyl-CoA) inside mitochondria.
Acetyl-CoA feeds carbon into the tricarboxylic acid (TCA) cycle and supplies the acetyl groups used to make acetylcholine. It is a metabolic intermediate, not a vitamin.
The TCA cycle oxidises acetyl groups and produces reduced electron carriers, which feed the respiratory chain.
Oxygen accepts electrons at the end of the chain. The resulting proton gradient drives ATP synthase, the enzyme that makes ATP.
During prolonged fasting, ketone bodies become an alternative brain fuel, but some glucose-dependent needs remain.
The GABA shunt
The GABA shunt links inhibitory neurotransmission to carbon metabolism.
Glutamate decarboxylase converts glutamate to gamma-aminobutyric acid (GABA). It needs pyridoxal phosphate, the active form of vitamin B6.
GABA transaminase converts GABA to succinic semialdehyde.
Succinic semialdehyde dehydrogenase converts this to succinate, which enters the TCA cycle.
Because carbon re-enters as succinate, the shunt bypasses the alpha-ketoglutarate dehydrogenase and succinyl-CoA synthetase steps.
Cofactors and carriers
Cofactor or carrier | What it does | Clinical link |
|---|---|---|
Thiamine pyrophosphate | Pyruvate and alpha-ketoglutarate dehydrogenase reactions | Deficiency impairs brain energy metabolism |
Nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) | Carry electrons in oxidation reactions | Regenerated by mitochondrial respiration |
Coenzyme A | Carries acyl groups | Forms acetyl-CoA and succinyl-CoA |
Pyridoxal phosphate | Amino-acid reactions, including GABA synthesis | Deficiency can make seizures more likely |
Folate derivatives | Transfer one-carbon units | Support nucleotide synthesis and methylation, with vitamin B12 |
Clinical relevance
Hypoxia (too little oxygen) or hypoglycaemia (low blood glucose) can impair the ATP-dependent ion pumps, causing confusion, seizures or coma. Psychiatric symptoms in this setting do not mean the cause is primarily psychiatric.