A possible mechanism of mitochondrial dysfunction during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid.
The dramatic increase in the arachidonic acid (AA) level in the brain is a well-known molecular event during cerebral ischemia. As mitochondria are known to be one possible site of the cell damage, the effects of AA on the respiratory activity of rat brain mitochondria were investigated in vitro using an oxygen electrode. In NAD-linked respiration, respiratory control ratio was decreased significantly by AA, with an IC50 of 6.0 microM. AA had the dual effect on mitochondrial respiration, a decrease in state 3 and uncoupled state and an increase in state 4 (i.e., uncoupling) as reported by Hillered and Chan (J. Neurosci. Res. 19, 94-100, 1988). Furthermore, we found that other unsaturated long-chain free fatty acids (C18:1-C18:3, C20:1-C20:5) also showed such a dual effect. Cyclooxygenase metabolites of AA such as prostaglandins (D2, E2, F2 alpha, E1) and thromboxane B2, and lipoxygenase metabolites such as leukotrienes (D4, B4) and 5- or 12-hydroperoxyeicosatetraenoic acid had no significant effect. The inhibition of the uncoupled state by AA was more marked in NAD-linked than that in FAD-linked respiration, while the degree of uncoupling by AA were the same in both respirations. In spectrophotometrical measurement, the reduction of cytochromes and flavo-protein was markedly inhibited by AA in NAD-linked respiration, but not in the FAD-linked one. In addition, the activity of cytochrome c oxidase was scarcely inhibited by AA. These data suggest that AA itself, not its metabolites, may inhibit mitochondrial ATP production during brain ischemia and that AA may act on the site(s) closely related to NAD-linked respiration, but not the FAD-linked one, in addition to its uncoupling effect.
Takeuchi
Y
Y
Department of Neuroscience, Osaka Bioscience Institute, Japan.
Morii
H
H
Tamura
M
M
Hayaishi
O
O
Watanabe
Y
Y
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002545:Brain Ischemia / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV