Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Neuroscience. 2021 Aug 1;468:68-74. doi: 10.1016/j.neuroscience.2021.06.003. Epub 2021 Jun 11.
Mitochondrial permeability transition pore (mPTP) opening is critical to mitochondrial apoptosis during ischemic injury. Sirtuin 3 (Sirt3) is a mitochondrial deacetylase known to play a major role in stress resistance and cell death. Our previous studies have shown that Sirt3 activates superoxide dismutase 2 and forkhead box O3a to reduce cellular reactive oxygen species. However, it is unclear the interaction between Sirt3 and mPTP and the roles they play in ischemic stroke. We used the middle cerebral artery occlusion (MCAO) model, a mouse model of stroke, to examine Sirt3 and mPTP-related protein levels. We then applied lentivirus packaged Sirt3 overexpression in HT22 cells, a mouse hippocampal neuronal cell line, to investigate the underlying mechanism. We found Sirt3 protein level was decreased in the penumbra area in MCAO mice, along with an increase in mPTP related proteins, namely voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocator 1 (ANT1). Sirt3 overexpression suppressed the increase in VDAC1, ANT1 and cleaved caspase 3 that were induced by the serum and glucose deprivation (SGD) condition. Our studies suggest that ischemic injury induced mPTP opening and apoptosis by reducing Sirt3. It helps to identify new therapeutic targets for ischemic stroke.
线粒体通透性转换孔（mPTP）的开放对于缺血性损伤期间的线粒体凋亡至关重要。Sirtuin 3（Sirt3）是一种线粒体去乙酰化酶，已知其在应激抵抗和细胞死亡中发挥重要作用。我们之前的研究表明，Sirt3 激活超氧化物歧化酶 2 和叉头框 O3a 以减少细胞内活性氧。然而，Sirt3 与 mPTP 之间的相互作用及其在缺血性中风中的作用尚不清楚。我们使用大脑中动脉闭塞（MCAO）模型，即中风的小鼠模型，检查了 Sirt3 和与 mPTP 相关的蛋白水平。然后，我们在 HT22 细胞（一种小鼠海马神经元细胞系）中应用包装有 Sirt3 过表达的慢病毒，以研究潜在的机制。我们发现，在 MCAO 小鼠的半影区中 Sirt3 蛋白水平降低，同时 mPTP 相关蛋白，即电压依赖性阴离子通道 1（VDAC1）和腺嘌呤核苷酸转位酶 1（ANT1）增加。Sirt3 过表达抑制了由血清和葡萄糖剥夺（SGD）条件诱导的 VDAC1、ANT1 和裂解的 caspase 3 的增加。我们的研究表明，缺血性损伤通过降低 Sirt3 诱导 mPTP 开放和细胞凋亡。这有助于确定缺血性中风的新治疗靶点。
