Intramitochondrial decarboxylation of glucose-derived pyruvate by PDHC (pyruvate dehydrogenase complex) is a principal source of acetyl-CoA, for mitochondrial energy production and cytoplasmic synthetic pathways in all types of brain cells. The inhibition of PDHC, ACO (aconitase) and KDHC (ketoglutarate dehydrogenase complex) activities by neurodegenerative signals such as aluminium, zinc, amyloid β-peptide, excess nitric oxide (NO) or thiamine pyrophosphate deficits resulted in much deeper losses of viability, acetyl-CoA and ATP in differentiated cholinergic neuronal cells than in non-differentiated cholinergic, and cultured microglial or astroglial cell lines. In addition, in cholinergic cells, such conditions caused inhibition of ACh (acetylcholine) synthesis and its quantal release. Furthermore, cholinergic neuronal cells appeared to be resistant to high concentrations of LPS (lipopolysaccharide). In contrast, in microglial cells, low levels of LPS caused severalfold activation of NO, IL-6 (interleukin 6) and TNFα (tumour necrosis factor α) synthesis/release, accompanied by inhibition of PDHC, KDHC and ACO activities, and suppression of acetyl-CoA, but relatively small losses in their ATP contents and viability parameters. Compounds that protected these enzymes against inhibitory effects of neurotoxins alleviated acetyl-CoA and ATP deficits, thereby maintaining neuronal cell viability. These data indicate that preferential susceptibility of cholinergic neurons to neurodegenerative insults may result from competition for acetyl-CoA between mitochondrial energy-producing and cytoplasmic ACh-synthesizing pathways. Such a hypothesis is supported by the existence of highly significant correlations between mitochondrial/cytoplasmic acetyl-CoA levels and cell viability/transmitter functions respectively.
Intracellular redistribution of acetyl-CoA, the pivotal point in differential susceptibility of cholinergic neurons and glial cells to neurodegenerative signals
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Andrzej Szutowicz, Hanna Bielarczyk, Anna Ronowska, Sylwia Gul-Hinc, Joanna Klimaszewska-Łata, Aleksandra Dyś, Marlena Zyśk, Tadeusz Pawełczyk; Intracellular redistribution of acetyl-CoA, the pivotal point in differential susceptibility of cholinergic neurons and glial cells to neurodegenerative signals. Biochem Soc Trans 1 August 2014; 42 (4): 1101–1106. doi: https://doi.org/10.1042/BST20140078
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