Citrate modifies iron toxicity in the yeast model of Friedreich
Ataxia.
Opal Chen, Shawn Hemenway, Jerry Kaplan
Department of Pathology, University of Utah, 30 N Medical Dr., Salt Lake
City, UT 84132, U.S.A.
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
mutant genes that can preserve respiratory activity in deltayfh1
cells. A deletion in CIT2, a peroxisomal citrate synthase, 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-iron toxicity was not restricted to
mitochondria but also occurred when iron accumulated in cytosol due to
impaired vacuolar iron storage. These results suggest that high levels
of citrate and iron may account for iron-mediated tissue damage.
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