title: Acetyl-CoA and acetylcholine metabolism in nerve terminal compartment of thiamine deficient rat brain.
abstract: The decrease of pyruvate and ketoglutarate dehydrogenase complex activities is the main cause of energy and acetyl-CoA deficits in thiamine deficiency-evoked cholinergic encephalopathies. However, disturbances in pathways of acetyl-CoA metabolism leading to appearance of cholinergic deficits remain unknown. Therefore, the aim of this work was to investigate alterations in concentration and distribution of acetyl-CoA and in acetylcholine metabolism in brain nerve terminals, caused by thiamine deficits. They were induced by the pyrithiamine, a potent inhibitor of thiamine pyrophosphokinase. The thiamine deficit reduced metabolic fluxes through pyruvate and ketoglutarate dehydrogenase steps, yielding deficits of acetyl-CoA in mitochondrial and cytoplasmic compartments of K-depolarized nerve terminals. It also inhibited indirect transport of acetyl-CoA though ATP-citrate lyase pathway being without effect on its direct Ca-dependent transport to synaptoplasm. Resulting suppression of synaptoplasmic acetyl-CoA correlated with inhibition of quantal acetylcholine release (r = 0.91, p = 0.012). On the other hand, thiamine deficiency activated non-quantal acetylcholine release that was independent of shifts in intraterminal distribution of acetyl-CoA. Choline acetyltransferase activity was not changed by these conditions. These data indicate that divergent alterations in the release of non-quantal and quantal acetylcholine pools from thiamine deficient nerve terminals could be caused by the inhibition of acetyl-CoA and citrate synthesis in their mitochondria. They in turn, caused inhibition of acetyl-CoA transport to the synaptoplasmic compartment through ATP-citrate lyase pathway yielding deficits of cholinergic functions.
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jankowska-Kulawy
authors.forename: Hanna
authors.initials: H
authors.lastname: Bielarczyk
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pawełczyk
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wróblewska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szutowicz
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure*; D019343:Citric Acid / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009411:Nerve Endings / Q000378:metabolism* / Q000648:ultrastructure; D011745:Pyrithiamine / Q000009:adverse effects; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000378:metabolism; D013832:Thiamine Deficiency / Q000209:etiology / Q000473:pathology*
chemical_list: D007656:Ketoglutaric Acids; D019343:Citric Acid; D019344:Lactic Acid; D011745:Pyrithiamine; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D007655:Ketoglutarate Dehydrogenase Complex; D000109:Acetylcholine