title: The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo.
abstract: The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-me-/- mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-me-/- erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-me-/- erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-me-/- erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo.
authors.affiliation: Department of Medicine, Obesity and Nutrition section, Mitochondria ARC, Evans Biomedical Research Center, Boston University School of Medicine, MA, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Hyde
authors.forename: M
authors.initials: M
authors.lastname: Liesa
authors.forename: A A
authors.initials: AA
authors.lastname: Elorza
authors.forename: W
authors.initials: W
authors.lastname: Qiu
authors.forename: S E
authors.initials: SE
authors.lastname: Haigh
authors.forename: L
authors.initials: L
authors.lastname: Richey
authors.forename: H K
authors.initials: HK
authors.lastname: Mikkola
authors.forename: T M
authors.initials: TM
authors.lastname: Schlaeger
authors.forename: O S
authors.initials: OS
authors.lastname: Shirihai
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D050980:GATA Transcription Factors / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D018384:Oxidative Stress; D050050:Protein Carbonylation; D013481:Superoxides
chemical_list: D018528:ATP-Binding Cassette Transporters; D050980:GATA Transcription Factors; D006454:Hemoglobins; D008665:Metalloporphyrins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013481:Superoxides; C410734:Abcb10 protein, mouse; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C421109:multidrug resistance-associated protein 1