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Human Molecular Genetics, 2003, Vol. 12, No. 8 879-889
DOI: 10.1093/hmg/ddg096
© 2003 Oxford University Press

Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1)

Emmanuel Lesuisse1,*, Renata Santos1, Berthold F. Matzanke2, Simon A. B. Knight3, Jean-Michel Camadro1 and Andrew Dancis3

1Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département de Biologie des Génomes, Institut Jacques Monod, Unité Mixte de Recherche 7592 CNRS-Universités Paris 6 and 7, 2 place Jussieu, F-75251 Paris cedex 05, France, 2University of Luebeck, Isotopes Laboratory TNF, Ratzeburger Allee 160, D-23538 Luebeck, Germany and 3Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA

Received December 20, 2002; Accepted February 7, 2003

The YFH1 gene is the yeast homologue of the human FRDA gene, which encodes the frataxin protein. Saccharomyces cerevisiae cells lacking the YFH1 gene showed very low cytochrome content. In {Delta}yfh1 strains, the level of ferrochelatase (Hem15p) was very low, as a result of transcriptional repression of HEM15. However, the low amount of Hem15p was not the cause of haeme deficiency in {Delta}yfh1 cells. Ferrochelatase, a mitochondrial protein, able to mediate insertion of iron or zinc into the porphyrin precursor, made primarily the zinc protoporphyrin product. Zinc protoporphyrin instead of haeme accumulated during growth of {Delta}yfh1 mutant cells and, furthermore, preferential formation of zinc protoporphyrin was observed in real time. The method for these studies involved direct presentation of porphyrin to mitochondria and to ferrochelatase of permeabilized cells with intact architecture, thereby specifically testing the iron delivery portion of the haeme biosynthetic pathway. The studies showed that {Delta}yfh1 mutant cells are defective in iron use by ferrochelatase. Mössbauer spectroscopic analysis showed that iron was present as amorphous nano-particles of ferric phosphate in {Delta}yfh1 mitochondria, which could explain the unavailability of iron for haeme synthesis. A high frequency of suppressor mutations was observed, and the phenotype of such mutants was characterized by restoration of haeme synthesis in the absence of Yfh1p. Suppressor strains showed a normal cytochrome content, normal respiration, but remained defective in Fe–S proteins and still accumulated iron into mitochondria although to a lesser extent. Yfh1p and Hem15p were shown to interact in vitro by Biacore studies. Our results suggest that Yfh1 mediates iron use by ferrochelatase.

* To whom correspondence should be addressed. Tel: +33 144276356; Fax: +33 144275716; Email: lesuisse{at}ijm.jussieu.fr


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