Pokhrel Suman, Heo Gwangbeom, Mathews Irimpan, Yokoi Shun, Matsui Tsutomu, Mitsutake Ayori, Wakatsuki Soichi, Mochly-Rosen Daria
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
Nat Commun. 2025 May 6;16(1):4187. doi: 10.1038/s41467-025-59434-6.
Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.
Fis1介导的动力相关蛋白1（Drp1）在线粒体上的定位以及过度的线粒体分裂发生在与氧化应激相关的人类疾病中。然而，尚不清楚Fis1如何检测氧化应激以及Fis1的哪些结构变化能够促使Drp1定位于线粒体。我们发现，Fis1中涉及α1螺旋的构象变化会暴露出其唯一的半胱氨酸，即Cys41。在氧化应激存在的情况下，活化的Fis1中暴露的Cys41会形成二硫键，并且Fis1共价同源二聚体通过增加Drp1向线粒体的募集而导致线粒体分裂增加。我们发现了一种小分子SP11，它通过与Cys41结合而仅与活化的Fis1结合，并且来自缺乏Cys41的基因工程细胞系的数据强烈表明Fis1同源二聚化在Drp1向线粒体募集和过度线粒体分裂中起作用。活化的Fis1-SP11复合物的结构进一步证实了这些与Cys41作为氧化应激传感器相关的见解。重要的是，SP11在氧化应激期间维持细胞内线粒体的完整性和功能，因此可能作为开发针对由Fis1介导的线粒体碎片化和功能障碍所引发疾病的治疗药物的候选分子。
