Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex

All raw and analyzed data in the manuscript "Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex". DOI: 10.1101/2024.10.22.619706 Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, Dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of perisynaptic astrocyte process (PAP) proteins, most notably gap junction protein Connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondria dynamics as a critical step in neurodevelopment.本数据集包含论文《线粒体分裂调控皮层星形胶质细胞形态发生与组织》的全部原始与分析数据，DOI：10.1101/2024.10.22.619706。功能异常的线粒体动态过程是儿童难治性癫痫等严重神经发育障碍的标志性特征，但胶质细胞线粒体在正常脑发育中的作用尚未得到充分阐明。本研究证实，在出生后皮层发育阶段，星形胶质细胞线粒体在向星形胶质细胞远端分支定植的同时会发生广泛的分裂。作为线粒体分裂的核心调控因子，动力相关蛋白1（Dynamin-related protein 1, Drp1）的缺失会降低线粒体向星形胶质细胞远端突起的定位效率，而这种线粒体定位异常会削弱星形胶质细胞的形态复杂度。功能层面实验显示，星形胶质细胞特异性条件性敲除Drp1会诱导星形胶质细胞活化，并破坏皮层内星形胶质细胞的正常组织架构。上述形态与组织缺陷同时伴随突触周围星形胶质细胞突起（perisynaptic astrocyte process, PAP）相关蛋白的丢失，其中最显著的为间隙连接蛋白Connexin 43。本研究揭示了线粒体分裂在协调星形胶质细胞形态发生与组织构建中的关键作用，表明星形胶质细胞线粒体动态调控是神经发育过程中的关键环节。