title: Phenotype-Dependent Interactions between N-acetyl-L-Aspartate and Acetyl-CoA in Septal SN56 Cholinergic Cells Exposed to an Excess of Zinc.
abstract: Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions.
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Marlena
authors.initials: M
authors.lastname: Zyśk
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bielarczyk
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Gul-Hinc
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dyś
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Gapys
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ronowska
authors.affiliation: Department of Molecular Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Sakowicz-Burkiewicz
authors.affiliation: Department of Laboratory Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Szutowicz
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D005110:Extracellular Space / Q000378:metabolism; D005991:Glycerol Kinase; D007658:Ketone Oxidoreductases / Q000378:metabolism; D051379:Mice; D020665:Septum of Brain / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000633:toxicity*
chemical_list: D002352:Carrier Proteins; D001224:Aspartic Acid; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate; C000179:N-acetylaspartate; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D000123:Acetyltransferases; C046791:aspartate N-acetyltransferase; D002795:Choline O-Acetyltransferase; C485945:Gk protein, rat; D005991:Glycerol Kinase; D015032:Zinc; D002118:Calcium
keywords: ATP; N-acetyl-L-aspartate; acetyl-CoA; aspartate N-acetyltransferase; cholinergic neurons neurotoxicity; zinc