title: Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis.
abstract: Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: J
authors.identifier: 0000000172685748
authors.initials: J
authors.lastname: Cho
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
authors.forename: J
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Lim
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Otsuka Maryland Medicinal Laboratories, Rockville, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Shiratsuchi
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: M-H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Physiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Chowdhury
authors.affiliation: Department of Physiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kasahara
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: 1] Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea [2] Department of Physiology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Oh
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Terada
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism; D006801:Humans; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*
chemical_list: D033742:Adenine Nucleotide Translocator 2; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases