Acetyl-CoA deficit in brain mitochondria in experimental thiamine deficiency encephalopathy.
Several pathologic conditions are known to cause thiamine deficiency, which induce energy shortages in all tissues, due to impairment of pyruvate decarboxylation. Brain is particularly susceptible to these conditions due to its high rate of glucose to pyruvate-driven energy metabolism. However, cellular compartmentalization of a key energy metabolite, acetyl-CoA, in this pathology remains unknown. Pyrithiamine-evoked thiamine deficiency caused no significant alteration in pyruvate dehydrogenase and 30% inhibition of α-ketoglutarate dehydrogenase activities in rat whole forebrain mitochondria. It also caused 50% reduction of the metabolic flux of pyruvate through pyruvate dehydrogenase, 78% inhibition of its flux through α-ketoglutarate dehydrogenase steps, and nearly 60% decrease of intramitochondrial acetyl-CoA content, irrespective of the metabolic state. State 3 caused a decrease in citrate and an increase in α-ketoglutarate accumulation. These alterations were more evident in thiamine-deficient mitochondria. Simultaneously thiamine deficiency caused no alteration of relative, state 3-induced increases in metabolic fluxes through pyruvate and α-ketoglutarate dehydrogenase steps. These data indicate that a shortage of acetyl-CoA in the mitochondrial compartment may be a primary signal inducing impairment of neuronal and glial cell functions and viability in the thiamine-deficient brain.
Jankowska-Kulawy
Agnieszka
A
Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
Bielarczyk
Hanna
H
Pawełczyk
Tadeusz
T
Wróblewska
Małgorzata
M
Szutowicz
Andrzej
A
D000105:Acetyl Coenzyme A / Q000172:deficiency*; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013832:Thiamine Deficiency / Q000201:enzymology* / Q000473:pathology; D014899:Wernicke Encephalopathy / Q000201:enzymology* / Q000473:pathology
D000105:Acetyl Coenzyme A