CCC1 Suppresses Mitochondrial Damage in the Yeast Model of Friedreich's Ataxia by Limiting Mitochondrial Iron Accumulation

Deletion of YFH1 inSaccharomyces cerevisiae leads to a loss of respiratory competence due to excessive mitochondrial iron accumulation. A suppressor screen identified a gene, CCC1, that maintained respiratory function in a Δyfh1 yeast strain regardless of extracellular iron concentration. CCC1 expression prevented excessive mitochondrial iron accumulation by limiting mitochondrial iron uptake rather than by increasing mitochondrial iron egress. Expression of CCC1 did not result in sequestration of iron in membranous compartments or cellular iron export.CCC1 expression in wild type cells resulted in increased expression of the high affinity iron transport system composed ofFET3 and FTR1, suggesting that intracellular iron is not sensed by the iron-dependent transcription factor Aft1p. Introduction of AFT1up, a constitutive allele of the iron transcription factor, AFT1, that also leads to increased high affinity iron transport did not prevent Δyfh1 cells from becoming respiratory-incompetent. Although the mechanism by whichCCC1 expression affects cytosolic iron is not known, the data suggest that excessive mitochondrial iron accumulation only occurs when cytosolic free iron levels are high.