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J. Biol. Chem., Vol. 281, Issue 6, 3354-3359, February 10, 2006

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Mitochondrial Reactive Oxygen Species in Mice Lacking Superoxide Dismutase 2

ATTENUATION VIA ANTIOXIDANT TREATMENT^*

From the Buck Institute for Age Research, Novato, California 94945

Mice that lack the mitochondrial form of superoxide dismutase (SOD2) incur severe pathologies and mitochondrial deficiencies, including major depletion of complex II, as a consequence of buildup of endogenous reactive oxygen species (Melov, S., Coskun, P., Patel, M., Tuinstra, R., Cottrell, B., Jun, A. S., Zastawny, T. H., Dizdaroglu, M., Goodman, S. I., Huang, T. T., Miziorko, H., Epstein, C. J., and Wallace, D. C. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 846–851 and Li, Y., Huang, T. T., Carlson, E. J., Melov, S., Ursell, P. C., Olson, J. L., Noble, L. J., Yoshimura, M. P., Berger, C., Chan, P. H., Wallace, D. C., and Epstein, C. J. (1995) Nat. Genet. 11, 376–381). These problems can be greatly attenuated or rescued by synthetic antioxidant treatment, such as with the catalytic antioxidant EUK189 (Hinerfeld, D., Traini, M. D., Weinberger, R. P., Cochran, B., Doctrow, S. R., Harry, J., and Melov, S. (2004) J. Neurochem. 88, 657–667). We have used heart mitochondria from sod2 null mice to better understand mitochondrial reactive oxygen species production both in the absence of SOD2 and following in vivo antioxidant treatment. Isolated heart mitochondria from 5-day-old sod2 null animals respiring on the complex II substrate succinate exhibited statistically significant higher levels of mitochondrial (157%, p < 0.01) but significantly less H₂O₂ (33%, p < 0.001) than wild type littermates. Treatment of sod2 nullizygous mice with EUK189 proportionately increased the levels of complex II and H₂O₂. Increased production of resulting from complex II normalization had no effect on steady state levels due to the rapid conversion to H₂O₂, a process presumably aided by the presence of the EUK189, an SOD mimetic.

Received for publication, August 22, 2005 , and in revised form, November 7, 2005.

^* This work was supported by National Institutes of Health Grant AG18679 (to S. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Nuffield Dept. of Obstetrics and Gynaecology, Womens Centre, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX6 9DU, UK.

² To whom correspondence should be addressed: Buck Inst. for Age Research, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2068; Fax: 415-209-2231; E-mail: smelov{at}buckinstitute.org.

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