The mitochondrial respiratory complex I is a target for 15-deoxy-delta12,14-prostaglandin J2 action.
The prostaglandin J2 derivative 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a very active compound with important effects on inflammation, apoptosis, and cell growth processes. To exert this broad range of effects, 15d-PGJ2 binds and alters the activity of diverse proteins, which consequently are postulated to be mediators of its action. Among them are the transcription factors peroxisome proliferator-activated receptor gamma and nuclear factor kappaB, which are thought to play an essential role in the antitumorigenic and anti-inflammatory actions of 15d-PGJ2. Here, we show that 15d-PGJ2, at micromolar concentrations, efficiently blocks state 3 oxygen consumption in intact nonsynaptic mitochondria isolated from rat cerebral cortex. This effect is attributable to the inhibition by this prostaglandin of the activity of the enzyme NADH-ubiquinone reductase (complex I) of the mitochondrial respiratory chain. In addition to this, 15d-PGJ2 dramatically increases the rate of reactive oxygen species generation by complex I. The inhibition by 15d-PGJ2 of complex I activity was abolished by dithiothreitol, which raises the possibility that adduct formation with a critical component of complex I accounts for the inhibitory effect of this prostaglandin. These results clearly identified mitochondrial complex I as a new target for 15d-PGJ2 actions.
Martínez
B
B
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
Pérez-Castillo
A
A
Santos
A
A
D000818:Animals; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; D015230:Prostaglandin D2; D010100:Oxygen