Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine.
Inhibition of mitochondrial complex I by 6-hydroxydopamine was studied in brain and liver preparations. NADH-quinone reductase activity of this complex from rat brain was inhibited by 6-hydroxydopamine partially uncompetitively with respect to NADH with a value of Ki 0.051 +/- 0.014 mM. The inhibition patterns for liver NADH-quinone reductase were more complicated than those obtained with the brain enzyme. Desferrioxamine behaved as a 'competitive' activator of complex I from both liver and brain (Ka = 2 mM and 0.02 mM, respectively). It also protected brain complex I against the inhibition by increasing Ki value about 10-fold. Furthermore, in the presence of desferrioxamine the residual activity of enzyme-substrate-inhibitor complex was increased. The data suggest that desferrioxamine does not compete directly with 6-hydroxydopamine for binding to the inhibitory site, but induces a conformation which is unfavorable for the binding of the inhibitor to the protein. The qualitative and quantitative differences between the behavior of the liver and brain enzyme complexes indicate that the assumption that the behavior of liver mitochondria can be used as a model for the situation in brain should be reconsidered.
Glinka
Y
Y
Department of Pharmacology, Rappaport Family Research Institute, NPF, Faculty of Medicine, Technion, Haifa, Israel.
Tipton
K F
KF
Youdim
M B
MB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003676:Deferoxamine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D016627:Oxidopamine; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D003676:Deferoxamine