title: Disruption of ATP-binding cassette B8 in mice leads to cardiomyopathy through a decrease in mitochondrial iron export.
abstract: Mitochondrial iron levels are tightly regulated, as iron is essential for the synthesis of Fe/S clusters and heme in the mitochondria, but high levels can cause oxidative stress. The ATP-binding cassette (ABC) transporter ABCB8 is a mitochondrial inner membrane protein with an unknown function. Here, we show that ABCB8 is involved in mitochondrial iron export and is essential for baseline cardiac function. Induced genetic deletion of ABCB8 in mouse hearts resulted in mitochondrial iron accumulation and cardiomyopathy, as assessed by echocardiography and invasive hemodynamics. Mice with ABCB8 deletion in the heart also displayed mitochondrial damage, and higher levels of reactive oxygen species and cell death. Down-regulation of ABCB8 in vitro resulted in decreased iron export from isolated mitochondria, whereas its overexpression had the opposite effect. Furthermore, ABCB8 is needed for the maturation of the cytosolic Fe/S proteins, as its deletion in vitro and in vivo led to decreased activity of cytosolic, but not mitochondrial, iron-sulfur-containing enzymes. These results indicate that ABCB8 is essential for normal cardiac function, maintenance of mitochondrial iron homeostasis and maturation of cytosolic Fe/S proteins. In summary, this report provides characterization of a protein involved in mitochondrial iron export.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL 60611, USA.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Marina
authors.initials: M
authors.lastname: Bayeva
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanefar
authors.forename: Vishnu
authors.initials: V
authors.lastname: Potini
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: R Kannan
authors.initials: RK
authors.lastname: Mutharasan
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.forename: Tejaswitha
authors.initials: T
authors.lastname: Jairaj Naik
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D006330:Heart Defects, Congenital / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D006334:Heart Function Tests; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats
chemical_list: C571883:ABCB8 protein, mouse; D018528:ATP-Binding Cassette Transporters; D007506:Iron-Sulfur Proteins; D007501:Iron