Yeast mitochondrial iron metabolism

Mitochondria utilize most of the cellular iron in the heme of the cytochromes and iron-sulfur proteins. Moreover, it has recently been shown that iron-sulfur clusters are synthesized in mitochondria. Friedreich ataxia is a neuropathy associated with mutations in a small mitochondrial protein of unknown function called frataxin. Frataxin has a yeast homolog, Yfh1p, which is currently used as a model for human frataxin.
YFH1 deletion elicits mitochondrial iron overload and low activity of the iron-sulfur proteins. Cellular iron homeostasis is altered as shown by the high increase in the expression of the genes involved in iron uptake from the culture medium. It has been proposed that mitochondrial dysfunction is caused by excess iron in mitochondria which generates toxic free radicals.
We have found that in yeast mitochondrial dysfunction is observed even in the absence of mitochondrial iron accumulation, indicating that iron toxicity is not the primary cause of the disease. Moreover, now we have evidence that biosynthesis of the iron-sulfur clusters is altered in null yfh1 mutants. Therefore, we suggest that frataxin plays a role in iron sulfur cluster biosynthesis.
We are also studying the mechanisms of iron import into mitochondria and have discovered two homologous mitochondrial solute carriers in the inner membrane that mediate iron import into the mitochondrial matrix.
Finally, using combinations of deletion strains in nuclear genes encoding mitochondrial antioxidant proteins, we plan to determine the role of yeast frataxin in oxidative stress.

Key publications

Foury, F. and Talibi, D. (2001). Mitochondrial iron homeostasis. A genome wide analysis of gene expression in a yeast frataxin deficient strain. J. Biol. Chem. 276, 7762-7768

Foury, F. (1999). Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain. FEBS Lett. 456, 281-284

Foury, F. and Cazzalini, O. (1997).Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicits iron accumulation in mitochondria. FEBS Lett. 411, 373-377

Koutnikova, H., Campuzano, V. Foury, F., Dollé, P., Cazzalini, O. and Koenig, M. (1997).Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genet. 16, 345-351