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J. Biol. Chem., Vol. 279, Issue 13, 12386-12395, March 26, 2004

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Saccharomyces cerevisiae Glutaredoxin 5-deficient Cells Subjected to Continuous Oxidizing Conditions Are Affected in the Expression of Specific Sets of Genes^*

Gemma Bellí, María Micaela Molina, José García-Martínez¶, José E. Pérez-Ortín¶, and Enrique Herrero||

From the Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Rovira Roure 44, 25198-Lleida and the ^¶Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas and Servicio de Chips de DNA-S.C.S.I.E., Universitat de València, 46100-Burjassot, Valencia, Spain

The Saccharomyces cerevisiae GRX5 gene codes for a mitochondrial glutaredoxin involved in the synthesis of iron/sulfur clusters. Its absence prevents respiratory growth and causes the accumulation of iron inside cells and constitutive oxidation of proteins. Null grx5 mutants were used as an example of continuously oxidized cells, as opposed to situations in which oxidative stress is instantaneously caused by addition of external oxidants. Whole transcriptome analysis was carried out in the mutant cells. The set of genes whose expression was affected by the absence of Grx5 does not significantly overlap with the set of genes affected in respiratory petite mutants. Many Aft1-dependent genes involved in iron utilization that are up-regulated in a frataxin mutant were also up-regulated in the absence of Grx5. BIO5 is another Aft1-dependent gene induced both upon iron deprivation and in grx5 cells; this links iron and biotin metabolism. Other genes are specifically affected under the oxidative conditions generated by the grx5 mutation. One of these is MLP1, which codes for a homologue of the Slt2 kinase. Cells lacking MLP1 and GRX5 are hypersensitive to oxidative stress caused by external agents and exhibit increased protein oxidation in relation to single mutants. This in turn points to a role for Mlp1 in protection against oxidative stress. The genes of the Hap4 regulon, which are involved in respiratory metabolism, are down-regulated in grx5 cells. This effect is suppressed by HAP4 overexpression. Inhibition of respiratory metabolism during continuous moderately oxidative conditions could be a protective response by the cell.

Received for publication, October 29, 2003 , and in revised form, December 24, 2003.

^* This work was supported in part by Grants GEN2001-4707-CO8-06 (to E. H.) and GEN2001-4707-CO8-07 from the Spanish Ministry of Science and Technology (to J. E. P.-O.) and by Grant 2001SGR00305 from the Generalitat de Catalunya (to E. H.). 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.

Recipient of a predoctoral grant from the Generalitat de Catalunya.

^|| To whom correspondence should be addressed: Dept. de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Rovira Roure 44, 25198-Lleida, Spain. Tel.: 34-973-702409; Fax: 34-973-702426; E-mail: enric.herrero{at}cmb.udl.es.

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