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Journal of Lipid Research, Vol. 46, 736-743, April 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

The mitochondrial respiratory complex I is a target for 15-deoxy-^12,14-prostaglandin J₂ action

B. Martínez^*, A. Pérez-Castillo^1, and A. Santos^1,*

^* Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, Madrid, Spain

¹ To whom correspondence should be addressed. e-mail: piedras3{at}med.ucm.es (A.S.); aperez{at}iib.uam.es (A.P-C.)

The prostaglandin J₂ derivative 15-deoxy-^12,14-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 and nuclear factor B, 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.

Abbreviations: DCFH, dichlorofluorescin; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; I-B, inhibitor B; NF-B, nuclear factor B; PGJ₂, prostaglandin J₂; PPAR, peroxisome proliferator-activated receptor ; ROS, reactive oxygen species

Supplementary key words respiratory chain • reactive oxygen species • cyclopentenone prostaglandins

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