Adrenodoxin reductase homolog (Arh1p) of yeast mitochondria required for iron homeostasis

Arh1p is an essential mitochondrial protein of yeast with reductase activit y. Here we show that this protein is involved in iron metabolism. A yeast s train was constructed in which the open reading frame was placed under the control of a galactose-regulated promoter. Protein expression was induced b y galactose and repressed to undetectable levels in the absence of galactos e, although cells grew quite well in the absence of inducer. Under noninduc ing conditions, cellular iron uptake was dysregulated, exhibiting a failure to repress in response to medium iron. Iron trafficking within the cell wa s also disturbed. Exposure of Arh1p-depleted cells to increasing iron conce ntrations during growth led to drastic increases in mitochondrial iron, ind icating a loss of homeostatic control. Activity of aconitase, a prototype F e-S protein, was deficient at all concentrations of mitochondrial iron, alt hough the protein level was unaltered, Heme protein deficiencies were exace rbated in the iron-loaded mitochondria, suggesting a toxic side effect of a ccumulated iron. Finally, a time course correlated the cellular depletion o f Arh1p with the coordinated appearance of various mutant phenotypes includ ing dysregulated cellular iron uptake, deficiency of Fe-S protein activitie s in mitochondria and cytoplasm, and deficiency of hemoproteins. Thus, Arh1 p is required for control of cellular and mitochondrial iron levels and for the activities of Fe-S cluster proteins.