AIF是线粒体定位蛋白，胁迫条件下可离开线粒体经胞浆入核诱发一类被称为parthanatos的程序性细胞死亡，导致脑损伤。目前该类细胞死亡的发生及调控研究匮乏。以往认为AIF一旦入核，细胞就难逃死亡。我们发现：缺氧或烷化剂都显著诱导AIF乙酰化；去乙酰化酶SirT1可负调控AIF并抑制缺氧、烷化剂及兴奋性氨基酸诱发的AIF依赖的细胞死亡，SirT1激活剂SIR1720可显著降低脑缺血缺氧损伤；AIF也与其它SirT1同源家族蛋白结合；SirT1敲除小鼠有视网膜病变发生，并伴随神经节细胞层AIF高度乙酰化。本课题拟研究AIF乙酰化修饰的发生及功能调控机制，解析SirT蛋白如何负调控AIF介导的细胞死亡及组织损伤，探讨SirT1激活剂用于阻断parthanatos、抵抗组织缺血缺氧损伤、或减缓视网膜病变的可行性。

AIF is a mitochondrial protein. Under stress conditions, AIF releases from mitochondria to the cytosol and to the nucleus where it induces parthanatos programmed cell death, which finally lead to brain injury. However, the mechanism and the regulation of AIF-induced cell death is still largely unknown. Early study suggested that parthanatos cannot be prevented once AIF translocated to the nucleus. Our primary studies identified that AIF can be modified by acetylation, and its acetylation levels are markedly upregulated under stress conditions including alkylating agents, hypoxia or excitative amino acid treatments. Moreover, SirT1 deacetylates AIF and inhibits cell death under stress conditions including alkylating agents, hypoxia and excitatory amino acids in an AIF-dependent manner. Furthermore, SirT1 activator SIR1720 pretreatment markedly attenuates hypoxic-ischemic brain injury in mice. We also observed that other SirT1 homeloges also interact with AIF in cells. In addition, the SirT1 knockdout mice showed retinopathy associated with abnormal AIF acetylation in the ganglion cell layer. In this proposal, we plan to study the regulatory mechanisms and functions of AIF acetylation, reveal how SirT proteins negatively regulates AIF-induced cell death and tissue damage, with aims to provide clues to new ways for using SirT1 activators to prevent parthanatos, downregulate hypoxic-ischemic tissue injury, or attenuate retinopathy.