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J. Biol. Chem., Vol. 283, Issue 13, 8318-8330, March 28, 2008

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Cellular and Mitochondrial Remodeling upon Defects in Iron-Sulfur Protein Biogenesis^*

Anja Hausmann, Birgit Samans, Roland Lill, and Ulrich Mühlenhoff¹

From the Institut für Zytobiologie und Zytopathologie, Philipps-Universität Marburg, Robert-Koch Strasse 6, 35032 Marburg and Institut für Molekularbiologie und Tumorforschung, Emil-Mannkopf-Strasse 2, Philipps-Universität Marburg, 35032 Marburg, Germany

Biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is an essential process involving the mitochondrial iron-sulfur cluster (ISC) assembly and export machineries and the cytosolic iron/sulfur protein assembly (CIA) apparatus. To define the integration of Fe/S protein biogenesis into cellular homeostasis, we compared the global transcriptional responses to defects in the three biogenesis systems in Saccharomyces cerevisiae using DNA microarrays. Depletion of a member of the CIA machinery elicited only weak (up to 2-fold) alterations in gene expression with no clear preference for any specific cellular process. In contrast, depletion of components of the mitochondrial ISC assembly and export systems induced strong and largely overlapping transcriptional responses of more than 200 genes (2–100-fold changes). These alterations were strikingly similar, yet not identical, to the transcriptional profiles developed upon iron starvation. Hence, mitochondria and their ISC systems serve as primary physiological regulators exerting a global control of numerous iron-dependent processes. First, ISC depletion activates the iron-responsive transcription factors Aft1/2p leading to increased cellular iron acquisition. Second, respiration and heme metabolism are repressed ensuring the balanced utilization of iron by the two major iron-consuming processes, iron-sulfur protein and heme biosynthesis. Third, the decreased respiratory activity is compensated by induction of genes involved in glucose acquisition. Finally, transcriptional remodeling of the citric acid cycle and the biosyntheses of ergosterol and biotin reflect the iron dependence of these pathways. Together, our data suggest a model in which mitochondria perform a global regulatory role in numerous cellular processes linked to iron homeostasis.

Received for publication, July 6, 2007 , and in revised form, January 18, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 593 and TR1, the Gottfried-Wilhelm Leibniz Program, Grant GRK 1216, Fonds der Chemischen Industrie, Deutsches Humangenomprojekt, and the Fritz-Thyssen-Stiftung. 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.

Microarray data are available from ArrayExpress at EBI, accession number E-MEXP-1215.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1, Tables SI–SIV, and additional references.

¹ To whom correspondence should be addressed. Tel.: 49-6421-2864171; Fax: 49-6421-2866414; E-mail: muehlenh{at}staff.uni-marburg.de.

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