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Human Molecular Genetics Advance Access published online on February 8, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl012
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 7, 2005
Revised February 1, 2006
Accepted February 1, 2006

Article

The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulphur cluster biogenesis

Corinne Pondarré 1, Brendan B. Antiochos 1, Dean R. Campagna 1, Stephen L. Clarke 2, Eric L. Greer 1, Kathryn M. Deck 2, Alice McDonald 3, An-ping Han 1, Amy Medlock 4, Jeffery L. Kutok 5, Sheila A. Anderson 2, Richard S. Eisenstein 2, and Mark D. Fleming 6 *

1 Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA
2 Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA 53706
3 Millennium Pharmaceuticals, Cambridge, MA, 01239, USA
4 Department of Biochemistry and Molecular Biology, and the Center for Metalloenzyme Studies, University of Georgia, Athens, Georgia, 30602, USA
5 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA
6 Department of Pathology, Children's Hospital and Harvard Medical School, Enders 1116.1, 320 Longwood Avenue, Boston, Massachusetts, 02115, USA

* To whom correspondence should be addressed.
Mark D. Fleming, E-mail: mark.fleming{at}childrens.harvard.edu


  Abstract

Proteins with iron-sulphur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia (XLSA/A) in humans, is a functional orthologue of yeast Atm1p and is predicted to export a mitochondrially-derived metabolite required for cytosolic Fe-S cluster assembly. Using an inducible Cre/loxP system to delete exons 9 and 10 of the Abcb7 gene, we examined the phenotype of mice deficient in Abcb7. We found that Abcb7 was essential in extraembryonic tissues early in gestation and that the mutant allele exhibits an X-linked parent-of-origin lethality effect. Furthermore, using X-chromosome inactivation assays and tissue specific deletions, Abcb7 was found to be essential for the development and function of numerous other cell types and tissues. A notable exception to this was liver, where loss of Abcb7 impaired cytosolic Fe-S cluster assembly but was not lethal. In this situation, control of iron regulatory protein 1 (IRP1), a key cytosolic modulator of iron metabolism, which is responsive to the availability of cytosolic Fe-S clusters, was impaired, and contributed to the dysregulation of hepatocyte iron metabolism. Altogether, these studies demonstrate the essential nature of Abcb7 in mammals, and further substantiate a central role for mitochondria in the biogenesis of cytosolic Fe-S proteins.


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