Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine.
The catecholaminergic neurotoxin 6-hydroxydopamine causes parkinsonian symptoms in animals and it has been proposed that reactive oxygen species and oxidative stress, enhanced by iron, may play a key role in its toxicity. The present results demonstrate that 6-hydroxydopamine reversibly inhibits complex I (NADH dehydrogenase) of brain mitochondrial respiratory chain in isolated mitochondria. 6-Hydroxydopamine itself, rather than its oxidative products, was responsible for the inhibition. Iron (III) did not enhance inhibition but decreased it by stimulating the nonenzyme oxidation of 6-hydroxydopamine. Inhibition was potentiated to some extent by calcium ion. Desferrioxamine protected complex I activity against the inhibition, but it was not due to its chelator or antioxidative properties. Desferrioxamine was also shown to activate NADH dehydrogenase in the absence of 6-hydroxydopamine. Activation of mitochondrial respiration by desferrioxamine may contribute to the enhanced neuron survival in the presence of desferrioxamine in some neurodegenerative conditions.
Glinka
Y
Y
Technion, Department of Pharmacology, Faculty of Medicine, Rappoport Family Research Institute, Haifa, Israel.
Tipton
K F
KF
Youdim
M B
MB
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D003676:Deferoxamine / Q000494:pharmacology; D004789:Enzyme Activation; D007501:Iron / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D016627:Oxidopamine; D007501:Iron; D009245:NADH Dehydrogenase; D003676:Deferoxamine