Wang Jing, Li Shuo, Xu Haidong, Xue Jie, Wan Xiaorui, Wu Weilong, Huang Jiani, Zhang Huiling, Qin Zhenghong, Wang Yan
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China.
Department of Pharmacology College of Pharmaceutical Sciences, Suzhou Key Laboratory of Aging and Nervous Diseases, and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China.
Biomed Pharmacother. 2025 Jun;187:118067. doi: 10.1016/j.biopha.2025.118067. Epub 2025 Apr 24.
Maintaining mitochondrial function plays a crucial role in preventing and treating neurodegenerative diseases. CDGSH iron-sulfur domain 1 (CISD1), a NEET family protein localized on the mitochondrial outer membrane, regulates mitochondrial iron transport. However, the precise mechanism by which CISD1 modulates mitochondrial Fe remains unclear. In this study, we examine the link between aberrant iron metabolism and mitochondrial dysfunction using in vivo and in vitro excitotoxicity models. Our study also clarifies how CISD1 modulates KA-mediated excitotoxic neuronal damage. Overexpression of CISD1 reverses KA-induced mitochondrial iron overload and dysfunction. KA significantly downregulate the mitochondrial protein deacetylase SIRT1. SRT1460 (SIRT1-specific agonist) mitigates mitochondrial iron overload and restore CISD1 expression levels. Altogether, CISD1 protects against excitotoxic injury by mitigating mitochondrial iron overload, thereby providing a potential therapeutic target for neurodegenerative diseases.
维持线粒体功能在预防和治疗神经退行性疾病中起着关键作用。CDGSH铁硫结构域1（CISD1）是一种位于线粒体外膜的NEET家族蛋白，可调节线粒体铁转运。然而，CISD1调节线粒体铁的精确机制尚不清楚。在本研究中，我们使用体内和体外兴奋性毒性模型研究异常铁代谢与线粒体功能障碍之间的联系。我们的研究还阐明了CISD1如何调节KA介导的兴奋性毒性神经元损伤。CISD1的过表达可逆转KA诱导的线粒体铁过载和功能障碍。KA显著下调线粒体蛋白脱乙酰酶SIRT1。SRT1460（SIRT1特异性激动剂）可减轻线粒体铁过载并恢复CISD1表达水平。总之，CISD1通过减轻线粒体铁过载来保护免受兴奋性毒性损伤，从而为神经退行性疾病提供了一个潜在的治疗靶点。
