Cholinergic Phenotypes of Acetyl-CoA with ATP-Citrate Lyase Link

TL;DR

This paper explores how acetyl-CoA, produced via ATP-citrate lyase, supports acetylcholine synthesis in cholinergic neurons, which is crucial for cognitive and motor functions.

Contribution

The paper highlights the novel role of ATP-citrate lyase in directly supplying acetyl units for acetylcholine synthesis in cholinergic neurons.

Findings

ATP-citrate lyase is preferentially localized in cholinergic neurons to support acetylcholine synthesis.

Lesions in cholinergic nuclei reduce acetylcholine levels and related enzyme activities in target brain areas.

Mitochondrial pyruvate dehydrogenase activity does not correlate with cholinergic innervation.

Abstract

Glycolysis-derived pyruvate is the almost exclusive source of acetyl-CoA for energy production in mitochondrial compartments of all types of neuronal and glial cells. Neurons utilize several times more glucose than glial cells due to their neurotransmitter functions. Cholinergic neurons that are responsible for cognitive functions require additional amounts of acetyl-CoA for acetylcholine-transmitter synthesis in their cytoplasmic compartment. It may be assured by preferential localization of ATP-citrate lyase (ACLY) in the cytoplasm of cholinergic neurons’ perikaryons and axonal terminals. This thesis is supported by the existence of strong regional and developmental correlations of ATP-citrate lyase and choline acetyltransferase (ChAT) activities and ACh levels in the brain. Electrolytic or chemical lesions of cholinergic nuclei cause proportional loss of the above parameters in the respective cortical target areas. On the other hand, the regional activity of mitochondrial pyruvate dehydrogenase complex (PDHC), which synthesizes nearly the whole pool of neuronal acetyl-CoA, displays no correlation with cholinergic innervation. It makes cholinergic neurons highly susceptible to brain pathologies impairing energy metabolism. Therefore, the ACLY pathway, which provides acetyl units directly to the site of acetylcholine synthesis in cholinergic nerve terminals, plays a key role in the maintenance of cholinergic neurotransmission. On the other hand, in cholinergic motor neurons, various ACLY–protein complexes are involved not only in neurotransmission but also in axonal transport of cholinergic elements from the perikaryon to cholinergic neuro-muscular junctions. This review presents findings supporting this thesis.

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