Cholinergic-receptor-independent dysfunction of mitochondrial respiratory chain enzymes, reduced mitochondrial transmembrane potential and ATP depletion underlie necrotic cell death induced by the organophosphate poison mevinphos.
Our current understanding of the nature of cell death that is associated with fatal organophosphate poisoning and the underlying cellular mechanisms is surprisingly limited. Taking advantage of the absence in an in vitro system of acetylcholinesterase, the pharmacological target of organophosphate compounds, the present study evaluated the hypothesis that the repertoire of cholinergic receptor-independent cellular events that underlie fatal organophosphate poisoning entails induction of mitochondrial dysfunction, followed by bioenergetic failure that leads to necrotic cell death because of ATP depletion. Pheochromocytoma PC12 cells incubated with the organophosphate pesticide mevinphos (0.4 or 4mumol) for 1 or 3h underwent a dose-related and time-dependent loss of cell viability that was not reversed by muscarinic (atropine) or nicotinic (mecamylamine) blockade. This was accompanied by depressed NADH cytochrome c reductase, succinate cytochrome c reductase or cytochrome c oxidase activity in the mitochondrial respiratory chain, reduced mitochondrial transmembrane potential, decreased ATP concentration, elevated ADP/ATP ratio, increased lactate dehydrogenase release and necrotic cell death. We conclude that Mev induces cholinergic receptor-independent necrotic cell death by depressing the activity of Complexes I to IV in the mitochondrial respiratory chain, eliciting reduction in mitochondrial transmembrane potential, depleting intracellular ATP contents and damaging cell membrane integrity.
Chan
J Y H
JY
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 81346, Taiwan, ROC.
Chan
S H H
SH
Dai
K Y
KY
Cheng
H L
HL
Chou
J L J
JL
Chang
A Y W
AY
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000494:pharmacology / Q000633:toxicity; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000187:drug effects*; D007306:Insecticides / Q000494:pharmacology / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008464:Mecamylamine / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008799:Mevinphos / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D016716:PC12 Cells / Q000187:drug effects* / Q000502:physiology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011950:Receptors, Cholinergic / Q000502:physiology; D014451:Ubiquinone / Q000494:pharmacology
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D018733:Nicotinic Antagonists; D011950:Receptors, Cholinergic; C517783:polyoxyethanyl 600 cholesteryl sebacate; D014451:Ubiquinone; D011092:Polyethylene Glycols; D008464:Mecamylamine; D008799:Mevinphos; D001285:Atropine; D000255:Adenosine Triphosphate; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV