The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis.
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.
Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Corinne
C
Pondarré
Brendan B
BB
Antiochos
Dean R
DR
Campagna
Stephen L
SL
Clarke
Eric L
EL
Greer
Kathryn M
KM
Deck
Alice
A
McDonald
An-Ping
AP
Han
Amy
A
Medlock
Jeffery L
JL
Kutok
Sheila A
SA
Anderson
Richard S
RS
Eisenstein
Mark D
MD
Fleming
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D003600:Cytosol / Q000378:metabolism*; D005804:Genes, Lethal; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D007501:Iron / Q000378:metabolism; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014960:X Chromosome / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2