Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in Saccharomyces cerevisiae

Friedreich's ataxia (FRDA) is a neurodegenerative disease typically caused by a deficiency of frataxin, a mitochondrial protein of unknown function, I n Saccharomyces cerevisiae, lack of the yeast frataxin homolog (YFH1 gene, Yfh1p polypeptide) results in mitochondrial iron accumulation, suggesting t hat frataxin is required for mitochondrial iron homeostasis and that FRDA r esults from oxidative damage secondary to mitochondrial iron overload, This hypothesis implies that the effects of frataxin deficiency could be influe nced by other proteins involved in mitochondrial iron usage, We show that Y fh1p interacts functionally with yeast mitochondrial intermediate peptidase (OCT1 gene, YMIP polypeptide), a metalloprotease required for maturation o f ferrochelatase and other iron-utilizing proteins. YMIP is activated by fe rrous iron in vitro and loss of YMIP activity leads to mitochondrial iron d epletion, suggesting that YMIP is part of a feedback loop in which iron sti mulates maturation of YMIP substrates and this in turn promotes mitochondri al iron uptake, Accordingly, YMIP is active and promotes mitochondrial iron accumulation in a mutant lacking Yfh1p (yfh1 Delta), while genetic inactiv ation of YMIP in this mutant (yfh1 Delta oct1 Delta) leads to a 2-fold redu ction in mitochondrial iron levels. Moreover, overexpression of Yfh1p resto res mitochondrial iron homeostasis and YMIP activity in a conditional oct1( ts) mutant, but does not affect iron levels in a mutant completely lacking YMIP (oct1 Delta). Thus, we propose that Yfh1p maintains mitochondrial iron homeostasis both directly, by promoting iron export, and indirectly, by re gulating iron levels and therefore YMIP activity, which promotes mitochondr ial iron uptake, This suggests that human MIP may contribute to the functio nal effects of frataxin deficiency and the clinical manifestations of FRDA.