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J. Biol. Chem., Vol. 279, Issue 48, 49883-49888, November 26, 2004

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Higher Respiratory Activity Decreases Mitochondrial Reactive Oxygen Release and Increases Life Span in Saccharomyces cerevisiae^*

Mario H. Barros, Brian Bandy, Erich B. Tahara¶, and Alicia J. Kowaltowski¶||

From the Departamento de Genética, Instituto de Biociências de Botucatu, Universidade Estadual Paulista, Botucatu, São Paulo 18618–000, Brazil, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada, and the ^¶Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, 05508–900, Brazil

Increased replicative longevity in Saccharomyces cerevisiae because of calorie restriction has been linked to enhanced mitochondrial respiratory activity. Here we have further investigated how mitochondrial respiration affects yeast life span. We found that calorie restriction by growth in low glucose increased respiration but decreased mitochondrial reactive oxygen species production relative to oxygen consumption. Calorie restriction also enhanced chronological life span. The beneficial effects of calorie restriction on mitochondrial respiration, reactive oxygen species release, and replicative and chronological life span could be mimicked by uncoupling agents such as dinitrophenol. Conversely, chronological life span decreased in cells treated with antimycin (which strongly increases mitochondrial reactive oxygen species generation) or in yeast mutants null for mitochondrial superoxide dismutase (which removes superoxide radicals) and for RTG2 (which participates in retrograde feedback signaling between mitochondria and the nucleus). These results suggest that yeast aging is linked to changes in mitochondrial metabolism and oxidative stress and that mild mitochondrial uncoupling can increase both chronological and replicative life span.

Received for publication, August 4, 2004 , and in revised form, September 8, 2004.

^* This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Natural Sciences and Engineering Research Council. 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.

^|| To whom correspondence should be addressed: Av. Prof. Lineu Prestes, 748, 05508–900, Cidade Universitária, São Paulo, SP, Brazil. Fax: 55-11-3815-5579; E-mail: alicia{at}iq.usp.br.

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