Sisalli Maria Josè, D'Apolito Elena, Cuomo Ornella, Lombardi Giovanna, Tufano Michele, Annunziato Lucio, Scorziello Antonella
Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II", Naples, Italy.
IRCCS Synlab SDN S.p.A, Via Gianturco 113, Naples, Italy.
Cell Death Dis. 2025 Jan 28;16(1):52. doi: 10.1038/s41419-025-07339-z.
Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection.
线粒体质量控制对于线粒体网络的稳态至关重要。线粒体自噬与生物发生之间的平衡对于减少脑缺血诱导的细胞死亡是必需的。缺血预处理（IPC）是中枢神经系统的一种适应性机制，可增加对致死性脑缺血的耐受性。已经证明，缺氧诱导的无七同源物2（Siah2）E3连接酶激活会影响线粒体动力学，促进线粒体蛋白的降解。因此，在本研究中，我们在IPC的体外和体内模型中研究了Siah2在IPC诱导的神经保护中的作用。为此，将皮质神经元暴露于30分钟的氧和葡萄糖剥夺（OGD，亚致死性损伤），然后再进行3小时的OGD加复氧（致死性损伤）。我们的结果表明，缺氧诱导的线粒体去极化在线粒体水平激活Siah2，并增加LC3-II蛋白表达，这是线粒体自噬的标志物，而复氧阶段可抵消这一作用。相比之下缺氧会降低过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的表达，PGC-1α是线粒体生物发生的标志物，而复氧后其表达增加，从而改善线粒体膜电位、线粒体钙含量和线粒体形态，进而在IPC中发挥神经保护作用。此外，Siah2沉默证实了这些结果。总的来说，这些发现表明，由于Siah2-E3连接酶的激活，线粒体自噬与线粒体生物发生之间的平衡可能在IPC诱导的神经保护中发挥作用。
