The mitochondrial respiratory complex I is a target for 15-deoxy-Δ12,14-prostaglandin J2 action

The prostaglandin J(2) derivative 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a very active compound with important effects on inflammation, apoptosis, and cell growth processes. To exert this broad range of effects, 15d-PGJ(2) 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 kappa B, which are thought to play an essential role in the antitumorigenic and anti-inflammatory actions of 15d-PGJ(2). Here, we show that 15d-PGJ(2), 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-PGJ(2) dramatically increases the rate of reactive oxygen species generation by complex I. The inhibition by 15d-PGJ(2) 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-PGJ(2) actions.