title: Disruption of the ATP-binding cassette B7 (ABTM-1/ABCB7) induces oxidative stress and premature cell death in Caenorhabditis elegans.
abstract: X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare inherited disorder characterized by mild anemia and ataxia. XLSA/A is caused by mutations in the ABCB7 gene, which encodes a member of the ATP-binding cassette transporter family. Studies in yeast, mammalian cells, and mice have shown that ABCB7 functions in the transport of iron-sulfur (Fe-S) clusters into the cytoplasm. To further investigate the mechanism of this disease, we have identified and characterized the Caenorhabditis elegans homologue of the ABCB7 gene, abtm-1. We have studied the function of abtm-1 using mutants and RNAi. abtm-1-depleted animals produce arrested embryos that have morphogenetic defects and unusual premature, putative apoptotic events. abtm-1(RNAi) animals also show accumulation of ferric iron and increased oxidative stress. Despite the increased level of oxidative stress in abtm-1(RNAi) animals, they have an increased life span. We observed accumulation of DAF-16/FOXO in the nuclei of affected animals and elevation of the expression of SOD-3, a well established target of DAF-16, which may explain the increased life span extension of these animals. abtm-1 is strongly expressed in tissues with a high energy demand, and abtm-1(RNAi) animals have phenotypes that reflect the need for abtm-1 in these tissues. Finally, we show that reducing the function of other genes involved in Fe-S cluster production produces similar phenotypic consequences to abtm-1 loss of function. Therefore, ablation of abtm-1 in C. elegans provides a model in which to investigate the mechanism underlying XLSA/A.
authors.affiliation: Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 46010 Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: González-Cabo
authors.forename: Arantxa
authors.initials: A
authors.lastname: Bolinches-Amorós
authors.forename: Juan
authors.initials: J
authors.lastname: Cabello
authors.forename: Sheila
authors.initials: S
authors.lastname: Ros
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno
authors.forename: Howard A
authors.initials: HA
authors.lastname: Baylis
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vázquez-Manrique
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D034622:RNA Interference; D000096923:Frataxin
chemical_list: D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D007501:Iron; D033862:Iron-Binding Proteins; D000096923:Frataxin; C560631:ABTM-1 protein, C elegans