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

Abstract

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.

• Authors: Corinne Pondarré, Brendan B Antiochos, Dean R Campagna, Stephen L Clarke, Eric L Greer, Kathryn M Deck, Alice McDonald, An-Ping Han, Amy Medlock, Jeffery L Kutok, Sheila A Anderson, Richard S Eisenstein, Mark D Fleming
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 15 Issue 6 Pg. 953-64 (Mar 15 2006) ISSN: 0964-6906 [Print] England
• PMID: 16467350 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Iron-Sulfur Proteins
• Mitochondrial Proteins
• Iron
• Iron Regulatory Protein 1
• Iron Regulatory Protein 2

Topics

• ATP-Binding Cassette Transporters (genetics, physiology)
• Animals
• Cell Line
• Cell Lineage (genetics)
• Cytosol (metabolism)
• Genes, Lethal
• Hepatocytes (metabolism, ultrastructure)
• Iron (metabolism)
• Iron Regulatory Protein 1 (metabolism)
• Iron Regulatory Protein 2 (metabolism)
• Iron-Sulfur Proteins (biosynthesis)
• Male
• Mice
• Mitochondrial Proteins (deficiency, genetics, physiology)
• X Chromosome (genetics)