Department of Shock and Transfusion, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, 400042, P. R. China.
Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P. R. China.
Adv Sci (Weinh). 2023 Dec;10(36):e2304885. doi: 10.1002/advs.202304885. Epub 2023 Nov 1.
Excessive mitochondrial fission following ischemia and hypoxia relies on the formation of contacts between the endoplasmic reticulum and mitochondria (ER-Mito); however, the specific mechanisms behind this process remain unclear. Confocal microscopy and time course recording are used to investigate how ischemia and hypoxia affect the activation of dynamin-related protein 1 (Drp1), a protein central to mitochondrial dynamics, ER-Mito interactions, and the consequences of modifying the expression of Drp1, shroom (Shrm) 4, and inverted formin (INF) 2 on ER-Mito contact establishment. Both Drp1 activation and ER-Mito contact initiation cause excessive mitochondrial fission and dysfunction under ischemic-hypoxic conditions. The activated form of Drp1 aids in ER-Mito contact initiation by recruiting Shrm4 and promoting actin bundling between the ER and mitochondria. This process relies on the structural interplay between INF2 and scattered F-actin on the ER. This study uncovers new roles of cytoplasmic Drp1, providing valuable insights for devising strategies to manage mitochondrial imbalances in the context of ischemic-hypoxic injury.
缺血缺氧后过度的线粒体裂变依赖于内质网和线粒体之间形成接触（ER-Mito）；然而，这一过程背后的具体机制仍不清楚。共聚焦显微镜和时程记录用于研究缺血缺氧如何影响与线粒体动力学、ER-Mito 相互作用以及改变 Drp1、Shrm4 和 INF2 表达的后果相关的 dynamin 相关蛋白 1（Drp1）的激活，研究 ER-Mito 接触建立。在缺血缺氧条件下，Drp1 的激活和 ER-Mito 接触的启动都会导致线粒体过度裂变和功能障碍。激活形式的 Drp1 通过募集 Shrm4 并促进 ER 和线粒体之间的肌动蛋白束状化来帮助 ER-Mito 接触的启动。这一过程依赖于 INF2 和 ER 上分散的 F-actin 之间的结构相互作用。这项研究揭示了细胞质 Drp1 的新作用，为设计策略以管理缺血缺氧损伤背景下的线粒体失衡提供了有价值的见解。
