The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain
| Autor: | Hanna Bielarczyk, S. Gul-Hinc, Anna Ronowska, Andrzej Szutowicz, Aleksandra Dyś, Joanna Klimaszewska-Łata, Marlena Zyśk, Agnieszka Jankowska-Kulawy |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
N-acetyl-L-aspartate Review Mitochondrion nerve growth factor lcsh:RC321-571 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine medicine metabolic compartmentation Glycolysis lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry acetyl-CoA Acetyl-CoA Neurodegeneration neurodegeneration protein acetylations medicine.disease Pyruvate dehydrogenase complex Choline acetyltransferase neuronal metabolism acetylcholine Pyruvate carboxylase Cell biology 030104 developmental biology chemistry Acetyltransferase 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Frontiers in Cellular Neuroscience, Vol 12 (2018) Frontiers in Cellular Neuroscience |
| ISSN: | 1662-5102 |
| Popis: | Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders. |
| Databáze: | OpenAIRE |
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