Apoptosis-inducing factor (AIF) is a family of conserved mitochondrial flavoproteins that have both vital and lethal functions in cells. The function and regulation of AIF-1, the original described and most abundant isoform, has been extensively studied, whereas three other AIF isoforms have not been further characterized. Here, we investigated the role of AIF-2, a brain-specific isoform of AIF, in an in vitro ischemia model in neuronal HT22 cells. We showed that AIF-2 was constitutively expressed in HT22 cells, and the oxygen and glucose deprivation (OGD) did not alter AIF-2 expression. Downregulation of AIF-2 with specific siRNA aggravated OGD-induced lactate dehydrogenase (LDH) release, apoptosis and loss of cell viability, whereas overexpression of AIF-2 through lentivirus transfection exerted the opposite effects. In OGD-treated cells, AIF-2 overexpression promoted the endogenous antioxidant enzyme activities, preserved mitochondrial membrane potential (MMP), inhibited cytochrome c release, and thereby prevented reactive oxygen species (ROS) generation and lipid peroxidation. In addition, AIF-2 significantly prevented the OGD-induced AIF-1 translocation from cytoplasm to the nuclei. In view of these considerations, AIF-2 might represent an ideal strategy to avoid AIF-1 associated neurotoxicity, and could be tested against brain ischemia in animal models.

凋亡诱导因子（AIF）是一类保守的线粒体黄素蛋白，在细胞中具有重要的生命力和致命的功能。AIF-1的功能和调控是最初描述的最丰富的同工型，目前已得到广泛研究，而其他三个AIF同工型尚未进一步表征。在这里，我们研究了神经元HT22细胞体外缺血模型中AIF-2（一种大脑特异性AIF异构体）的作用。我们表明，AIF-2在HT22细胞中组成性表达，并且氧和葡萄糖剥夺（OGD）不会改变AIF-2的表达。用特异性siRNA下调AIF-2会加剧OGD诱导的乳酸脱氢酶（LDH）的释放，凋亡和细胞活力的丧失，而通过慢病毒转染使AIF-2的过表达发挥相反的作用。在OGD处理的细胞中，AIF-2的过表达促进了内源性抗氧化酶的活性，保留了线粒体膜电位（MMP），抑制了细胞色素c的释放，从而阻止了活性氧（ROS）的产生和脂质过氧化。此外，AIF-2显着阻止了OGD诱导的AIF-1从细胞质到细胞核的转运。鉴于这些考虑，AIF-2可能代表一种避免AIF-1相关神经毒性的理想策略，并且可以在动物模型中针对脑缺血进行测试。AIF-2显着阻止了OGD诱导的AIF-1从细胞质到细胞核的转运。鉴于这些考虑，AIF-2可能代表一种避免AIF-1相关神经毒性的理想策略，并且可以在动物模型中针对脑缺血进行测试。AIF-2显着阻止了OGD诱导的AIF-1从细胞质到细胞核的转运。鉴于这些考虑，AIF-2可能代表一种避免AIF-1相关神经毒性的理想策略，并且可以在动物模型中针对脑缺血进行测试。