INSERM U848, Villejuif, France.
Cell Death Differ. 2010 Jul;17(7):1155-66. doi: 10.1038/cdd.2009.211. Epub 2010 Jan 29.
Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity.
凋亡诱导因子（AIF）在神经元中具有重要的支持作用和潜在的致死作用。在正常生理条件下，AIF 是一种重要的氧化还原活性线粒体酶，而在病理情况下，它从线粒体易位到受损神经元的细胞核，并介导凋亡染色质浓缩和细胞死亡。在这项研究中，我们揭示了 AIF 的一种脑特异性同工型 AIF2 的存在，其表达随着神经元前体细胞的分化而增加。AIF2 来自于利用替代外显子 2b，但使用与普遍存在的 AIF1 同工型相同的其余 15 个外显子。AIF1 和 AIF2 以相似的方式被导入线粒体，在其中它们锚定在内膜面向膜间隙。然而，AIF2 中编码的外显子 2b 中的线粒体内膜分拣信号比 AIF1 更疏水，表明 AIF2 比 AIF1 具有更强的膜锚定。与 AIF1 相比，AIF2 在用非离子型去污剂或碱性 pH 值处理时更难从线粒体中解吸。此外，AIF2 与 AIF1 二聚化，从而阻止其从线粒体中释放。相反，可以想象，神经元特异性 AIF 同工型 AIF2 可能被“设计”为保留在线粒体中，并最小化其潜在的神经毒性活性。
