Nerve growth factor and acetyl-L-carnitine evoked shifts in acetyl-CoA and cholinergic SN56 cell vulnerability to neurotoxic inputs.
Different groups of brain cholinergic neurons display variable susceptibility to similar neurotoxic inputs. The aim of this work was to find out whether changes in cholinergic phenotype may alter the availability of acetyl-CoA in mitochondrial compartment and thereby the viability of cholinergic neurons. Cyclic AMP (cAMP) and retinoic acid caused differentiation (DC) of T17 TrkA(+) cholinergic neuroblastoma cells. In addition, it increased the choline acetyltransferase (ChAT) activity, Ca(2+) accumulation and cytoplasmic acetyl-CoA level, but decreased mitochondrial acetyl-CoA and cell resistance to amyloid-beta(25-35) (Abeta) toxicity. Nerve growth factor (NGF) caused similar alterations in the nondifferentiated cells (NC). On the other hand, in DC NGF suppressed ChAT activity and elevated mitochondrial level of acetyl-CoA but also caused a further increase of Ca(2+) content and cell susceptibility to Abeta. The significant inverse correlation was found between ChAT activity and mitochondrial levels of acetyl-CoA. Abeta markedly reduced the expression of cholinergic phenotype, acetyl-CoA content, and viability of DC. These effects were absent or much less pronounced in NC. Acetyl-L-carnitine reversed suppressing effects of Abeta on acetyl-CoA levels and ChAT activity but did not reverse increased mortality in DC. Presented data indicate that increased transmitter activity in highly differentiated cholinergic neurons, decreased acetyl-CoA level in their mitochondrial compartment, and increased Ca(2+) accumulation can make them more prone to neurotoxic conditions. Phenotype-dependent changes in intracellular distribution of acetyl-CoA thus play an important role in regulation of viability and transmitter function in brain cholinergic neurons.
Szutowicz
Andrzej
A
Department of Laboratory Medicine, Medical University of Gdańsk, Debinki 7 str., 80-211 Gdańsk, Poland. aszut@amg.gda.pl
Bielarczyk
Hanna
H
Gul
Sylwia
S
Zieliński
Piotr
P
Pawełczyk
Tadeusz
T
Tomaszewicz
Maria
M
D000108:Acetylcarnitine / Q000494:pharmacology*; D000109:Acetylcholine / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D004347:Drug Interactions; D006836:Hydro-Lyases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009447:Neuroblastoma; D020917:Receptor, trkA / Q000502:physiology; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology; D014343:Trypan Blue
D016229:Amyloid beta-Peptides; D014212:Tretinoin; D000108:Acetylcarnitine; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D002795:Choline O-Acetyltransferase; D002950:Citrate (si)-Synthase; D020917:Receptor, trkA; D006836:Hydro-Lyases; C045581:lactate dehydratase; D014343:Trypan Blue; D000109:Acetylcholine; D002118:Calcium