Genetic analysis of iron citrate toxicity in yeast: implications for mammalian iron homeostasis.
Deletion of the yeast homologue of frataxin, YFH1, results in mitochondrial iron accumulation and respiratory deficiency (petite formation). We used a genetic screen to identify mutants that modify iron-associated defects in respiratory activity in Deltayfh1 cells. A deletion in the peroxisomal citrate synthase CIT2 in Deltayfh1 cells decreased the rate of petite formation. Conversely, overexpression of CIT2 in Deltayfh1 cells increased the rate of respiratory loss. Citrate toxicity in Deltayfh1 cells was dependent on iron but was independent of mitochondrial respiration. Citrate toxicity was not restricted to iron-laden mitochondria but also occurred when iron accumulated in cytosol because of impaired vacuolar iron storage. These results suggest that high levels of citrate may promote iron-mediated tissue damage.
Chen
Opal S
OS
Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Hemenway
Shawn
S
Kaplan
Jerry
J
D002950:Citrate (si)-Synthase / Q000502:physiology; D019343:Citric Acid / Q000633:toxicity*; D005656:Fungal Proteins / Q000502:physiology; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron / Q000378:metabolism* / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C079379:RTG2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D019343:Citric Acid; D007501:Iron; D002950:Citrate (si)-Synthase