半胱氨酸脱硫酶NFS1从线粒体转位到细胞核调控脑缺血再灌注损伤的作用及机制研究

脑缺血再灌注（I/R）损伤是缺血性脑卒中治疗的重点。细胞代谢在I/R损伤中发挥重要调控作用。线粒体作为细胞的代谢中心，在应激情况下，其部分蛋白可进入细胞核维持细胞的稳态。脑I/R后，线粒体中的蛋白是否可以进入细胞核发挥调控作用，尚不清楚。我们近期首次发现：半胱氨酸脱硫酶NFS1在I/R后定位由线粒体转至细胞核；线粒体中的NFS1在缺氧缺糖再灌注（OGD/R）后发生琥珀酰化修饰；敲减NFS1导致神经元死亡增加，加剧脑I/R损伤。因此，我们推断：脑I/R后，神经元线粒体中的NFS1发生琥珀酰化修饰，从线粒体转位到细胞核，通过结合响应I/R刺激的转录因子，促进抗氧化及维持线粒体功能等基因的转录，发挥神经保护作用。本项目拟阐明NFS1从线粒体转位到细胞核的机制；揭示细胞核中的NFS1促进OGD/R后神经元存活的机制；探究NFS1对脑I/R损伤的影响。预期成果将为临床治疗脑I/R损伤提供重要线索。

Cerebral ischemia-reperfusion (I/R) injury is the key point of ischemic stroke treatment. Cell metabolism changes greatly after cerebral I/R. As the center of the cell metabolism, some mitochondrial proteins can enter the nucleus under certain stresses, and play important roles in the nucleus to maintain cell homeostasis. Till now, whether proteins in the mitochondria can translocate into the nucleus to regulate cerebral I/R-induced injury is still unclear. Recently, we discovered for the first time that, cysteine desulfurase NFS1 translocated from the mitochondria to the nucleus after I/R; NFS1 in the mitochondria was modified by succinylation after oxygen-glucose deprivation and reoxygenation (OGD/R); Knockdown of NFS1 led to increased neuronal death which further aggravated cerebral I/R-induced injury. Therefore, we inferred that mitochondrial NFS1 undergoes succinylation modification after I/R, and translocates from mitochondria to the nucleus. The nucleus NFS1 may bind transcription factors that respond to I/R injury to promote the transcription of genes such as antioxidant genes and mitochondria homeostasis-related genes, which eventually exerts neuroprotective effects. This project intends to clarify the mechanism of NFS1 translocation from mitochondria to the nucleus after I/R; reveal the mechanism by which NFS1 promotes neuronal survival in the nucleus after OGD/R; explore the effects of NFS1 on cerebral I/R-induced injury. These expected results will provide important clues for the clinical treatment of cerebral I/R-induced injury.