Cho J, Seo J, Lim C H, Yang L, Shiratsuchi T, Lee M-H, Chowdhury R R, Kasahara H, Kim J-S, Oh S P, Lee Y J, Terada N
Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA.
Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
Cell Death Differ. 2015 Sep;22(9):1437-50. doi: 10.1038/cdd.2014.230. Epub 2015 Jan 23.
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.
腺嘌呤核苷酸转位酶（ANTs）通过线粒体内膜转运ADP和ATP，因此在真核细胞的能量代谢中发挥着至关重要的作用。小鼠有三种ANT旁系同源物，即Ant1（Slc25a4）、Ant2（Slc25a5）和Ant4（Slc25a31），它们以组织依赖性方式表达。虽然敲除小鼠的Ant1和Ant4基因已被表征，分别导致运动不耐受和雄性不育，但普遍表达的Ant2基因在动物发育中的作用尚未得到充分证实。在这里，我们通过基因靶向破坏产生了Ant2低表达小鼠，其中Ant2的表达大幅减少。这些小鼠除了出现苍白表型和出生率降低外，胚胎发育明显正常。然而，出生后生长严重迟缓，伴有大细胞性贫血、B淋巴细胞减少、乳酸性酸中毒和胃胀气，并在4周内死亡。Ant2缺失通过增加活性氧和过早死亡导致红系前体细胞成熟停滞，从而以细胞自主方式引起贫血。B淋巴细胞发育同样受到Ant2缺失的影响，脾细胞的最大呼吸能力和细胞ATP水平降低，同时伴随着线粒体通透性转换孔开放的细胞死亡增加。相比之下，髓系、巨核细胞和T淋巴细胞谱系显然保持完整。红系和B细胞发育可能特别容易受到Ant2缺失介导的线粒体功能障碍和氧化应激的影响。
