癫痫是弥漫性低级别胶质瘤（DLGG；弥漫性少突神经胶质瘤和星形细胞瘤的统称）的常见并发症，严重影响患者的生活质量。 DLGG 致癫痫性可能主要是由肿瘤和新皮质之间的相互作用产生的。神经元从细胞外环境摄取功能失调的线粒体可导致神经元放电异常。在可以跨质膜迁移的神经胶质瘤中经常观察到线粒体功能障碍。在这里，我们研究了 Rho GTP 酶激活蛋白 44 (RICH2) 在线粒体动力学和 DLGG 相关癫痫中的作用。我们使用免疫组织化学研究了人 DLGG 组织中线粒体和 RICH2 表达之间的关联。我们通过电生理学检查了裸鼠神经胶质瘤模型中 RICH2 与癫痫之间的关联。通过单细胞荧光显微镜评估RICH2对线粒体形态和钙运动的影响。进行定量 RT-PCR (qRT-PCR) 和蛋白质印迹分析来表征 RICH2 诱导的与线粒体动力学、有丝分裂发生和线粒体功能相关的基因的表达变化。我们发现少突胶质细胞瘤中的 RICH2 表达高于星形细胞瘤，并且与患者更好的预后和更高的癫痫发生率相关。线粒体的表达可能与临床 DLGG 相关癫痫有关，并因 RICH2 过表达而减少。 RICH2可以促进致瘤裸鼠DLGG相关癫痫的发生。 RICH2 过表达可能通过下调 MFN-1/MFN-2 水平减少钙流和线粒体从神经胶质瘤细胞（SW1088 和 U251）释放到细胞外环境，这表明线粒体融合减少。此外，我们观察到线粒体转运至神经元（从神经胶质瘤细胞释放并转运至神经元）的减少，这可以解释由于神经保护减少而导致 DLGG 相关癫痫发病率较高的原因。此外，RICH2 下调 MAPK/ERK/HIF-1 通路。总之，这些结果表明，RICH2 可以通过以下方式促进癫痫：(i) 通过 MFN 下调和 Drp-1 上调抑制线粒体融合； (ii) 改变 MAPK/ERK/Hif-1 信号轴。 RICH2 可能是治疗 DLGG 相关癫痫的潜在靶点。版权所有 © 2023。由 Elsevier Inc. 出版。

Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of patients. DLGG epileptogenicity may primarily be generated by interactions between the tumor and the neocortex. Neuronal uptake of dysfunctional mitochondria from the extracellular environment can lead to abnormal neuronal discharge. Mitochondrial dysfunction is frequently observed in gliomas that can transmigrate across the plasma membranes. Here, we examined the role of the Rho GTPase-activating protein 44 (RICH2) in mitochondrial dynamics and DLGG-related epilepsy. We investigated the association between mitochondrial and RICH2 expression in human DLGG tissues using immunohistochemistry. We examined the association between RICH2 and epilepsy in nude mouse glioma models by electrophysiology. The effect of RICH2 on mitochondrial morphology and calcium motility were assessed by single cell fluorescence microscopy. Quantitative RT-PCR (qRT-PCR) and Western blot analysis were performed to characterize RICH2 induced expression changes in the genes related to mitochondrial dynamics, mitogenesis and mitochondrial function. We found that RICH2 expression was higher in oligodendroglioma than in astrocytoma and was correlated with better prognosis and higher epilepsy rate in patients. The expression of mitochondria may be associated with clinical DLGG-related epilepsy and reduced by RICH2 overexpression. And RICH2 could promote DLGG-related epilepsy in tumorigenic nude mice. RICH2 overexpression decreased calcium flow and the mitochondria released from glioma cells (SW1088 and U251) into the extracellular environment, potentially via downregulation of MFN-1/MFN-2 levels which suggests reduced mitochondrial fusion. In addition, we observed decreased mitochondrial trafficking into neurons (released from glioma cells and trafficked into neurons), which could explain the higher incidence of DLGG-related epilepsy due to reduced neuroprotection. Furthermore, RICH2 downregulated MAPK/ERK/HIF-1 pathway. In conclusion, these results suggest that RICH2 could promote epilepsy by (i) inhibiting mitochondrial fusion via MFN downregulation and Drp-1 upregulation; (ii) altering the MAPK/ERK/Hif-1 signaling axis. RICH2 may be a potential target in the treatment of DLGG-related epilepsy.Copyright © 2023. Published by Elsevier Inc.