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J Biol Chem, Vol. 274, Issue 53, 37709-37716, December 31, 1999

The Regulation of Mitochondrial Oxygen Uptake by Redox Reactions Involving Nitric Oxide and Ubiquinol^*

Juan José Poderoso^§, Constanza Lisdero, Francisco Schöpfer, Natalia Riobó, María Cecilia Carreras, Enrique Cadenas^¶, and Alberto Boveris

From the  Laboratory of Oxygen Metabolism, University Hospital, School of Medicine, University of Buenos Aires, Córdoba 2351, 1120 Buenos Aires, Argentina, the ^¶ Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089-9121, and the  Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, 1120 Buenos Aires, Argentina

The reversible inhibitory effects of nitric oxide (·NO) on mitochondrial cytochrome oxidase and O₂ uptake are dependent on intramitochondrial ·NO utilization. This study was aimed at establishing the mitochondrial pathways for ·NO utilization that regulate O₂ generation via reductive and oxidative reactions involving ubiquinol oxidation and peroxynitrite (ONOO^-) formation. For this purpose, experimental models consisting of intact mitochondria, ubiquinone-depleted/reconstituted submitochondrial particles, and ONOO^--supplemented mitochondrial membranes were used.

The results obtained from these experimental approaches strongly suggest the occurrence of independent pathways for ·NO utilization in mitochondria, which effectively compete with the binding of ·NO to cytochrome oxidase, thereby releasing this inhibition and restoring O₂ uptake. The pathways for ·NO utilization are discussed in terms of the steady-state levels of ·NO and O₂ and estimated as a function of O₂ tension. These calculations indicate that mitochondrial ·NO decays primarily by pathways involving ONOO^- formation and ubiquinol oxidation and, secondarily, by reversible binding to cytochrome oxidase.

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^* This work was supported by Research Grants ME 047 and TB011 from the University of Buenos Aires, Agency for Promotion of Scientific and Technological Development Grants 01608 and 12372, the Fundación Perez Companc (Buenos Aires, Argentina), and National Institutes of Health Grant 1RO1AG16718-01.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ To whom correspondence should be addressed. Tel. and Fax: 54-114-508-3983; E-mail: jpoderos@fmed.uba.ar.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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