Metabolic remodeling in frataxin-deficient yeast is mediated by Cth2 and Adr1.

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.
Mesh Terms:
Aconitate Hydratase, Alcohol Dehydrogenase, Cell Nucleus, DNA-Binding Proteins, Doxycycline, Gene Expression Regulation, Fungal, Genes, Fungal, Glutaredoxins, Green Fluorescent Proteins, Iron-Binding Proteins, Models, Biological, Oligonucleotide Array Sequence Analysis, Oxidative Stress, Protein Transport, Proteome, Proteomics, Reproducibility of Results, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factors, Tristetraprolin
Biochim. Biophys. Acta Dec. 01, 2013; 1833(12);3326-37 [PUBMED:24100161]
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