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Frataxin is a mitochondrial protein involved in iron metabolism whose deficiency in humans causes Friedreich
ataxia. We performed transcriptomic and proteomic analyses of conditional Yeast Frataxin Homologue (Yfh1)
mutants (tetO7-YFH1) to investigate metabolic remodeling upon Yfh1 depletion. These studies revealed that
Yfh1 depletion leads to downregulation of many glucose-repressed genes. Most of them were Adr1 targets, a
key transcription factor required for growth in non-fermentable carbon sources. Using a GFP-tagged Adr1, we
observed that Yfh1 depletion promotes the export of Adr1 from the nucleus to the cytosol without affecting its
protein levels. This effect was also observed upon H2O2 treatment, but not by iron overload/starvation, indicating
the presence of a regulatory pathway involved in Adr1 export and inactivation upon stress conditions. We also
observed that CTH2, a gene involved in the mRNA degradation of several iron-containing enzymes, was induced
upon Yfh1 depletion. Accordingly, decreased levels of aconitase and succinate dehydrogenase were observed.
Nevertheless, their levels were maintained in a Δcth2 mutant even in the absence of Yfh1. From these results
we can conclude that, in addition to altering iron homeostasis, frataxin depletion involves drastic metabolic
remodeling governed by Adr1 and Cth2 that finally leads to downregulation of iron–sulfur proteins and other
proteins involved in respiratory metabolism.
This work was supported by grants to J.R. BFU2010-19193, and CSD2007-00020 Consolider Ingenio 2010 fromMinisterio de Economia y Competitividad (Spain), SGR2009-00196 from the Generalitat de Catalunya and to J.T. from La Marató de TV3 2010. |
