Human Molecular Genetics Advance Access originally published online on February 8, 2006
Human Molecular Genetics 2006 15(6):953-964; doi:10.1093/hmg/ddl012
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The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron–sulfur cluster biogenesis
1Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA, 2Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, USA, 3Millennium Pharmaceuticals, Cambridge, MA 01239, USA, 4Department of Biochemistry and Molecular Biology, The Center for Metalloenzyme Studies, University of Georgia, Athens, GA 30602, USA and 5Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed at: Department of Pathology, Children's Hospital and Harvard Medical School, Enders 1116.1, 320 Longwood Avenue, Boston, MA 02115, USA. Email: mark.fleming{at}childrens.harvard.edu
Received December 7, 2005; Accepted February 1, 2006
Proteins with iron–sulfur (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 in humans, is a functional ortholog 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 extra-embryonic 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, 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.
These authors contributed equally.
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