Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria.
We recently showed that melatonin counteracted mitochondrial oxidative stress and increased the activity of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes both in vivo and in vitro. To further clarify these effects, we studied here the activity of OXPHOS enzymes and the synthesis of ATP in rat liver and brain mitochondria in vitro. In sub-mitochondrial particles, melatonin increases the activity of the complexes I and IV dose-dependently, the effect being significant between 1 and 10nM. Blue native-PAGE followed by histochemical analysis of the OXPHOS enzymes further showed the melatonin-induced increase of complex I activity. Titration studies show that melatonin counteracts the partial inhibition of complex IV induced by 5 microM potassium cyanide. However, melatonin (up to 5mM) was unable to recover the activity of complex IV when it was completely blocked by 100 microM cyanide. These data suggest that the indoleamine could stimulate the activity of the non-inhibited part of the complex IV. Melatonin also increases the production of ATP in control mitochondria and counteracts the cyanide-induced inhibition of ATP synthesis. These results provide new hormonal mechanism regulating mitochondrial homeostasis and may explain, at least in part, the anti-aging and neuroprotective properties of melatonin.
Martín
Miguel
M
Departamento de Fisiología, Instituto de Biotecnología, Universidad de Granada, E-18012 Granada, Spain.
Macías
Manuel
M
León
Josefa
J
Escames
Germaine
G
Khaldy
Houda
H
Acuña-Castroviejo
Daríos
D
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism
D009097:Multienzyme Complexes; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D008550:Melatonin; D011190:Potassium Cyanide