The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.

中文翻译：

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硝呋嗪挽救了疾病模型中CHCHD10相关 MICOS 缺陷引起的有害影响


在 CHCHD10 基因中鉴定出点突变 （p.Ser59Leu） 是线粒体功能障碍可引发运动神经元疾病的第一个遗传证据。从那时起，我们已经证明这种突变导致维持线粒体嵴结构的线粒体接触位点和嵴组织系统 （MICOS） 复合物的瓦解。在这里，我们生成了模拟 MICOS 不稳定性的酵母突变菌株，并使用它们来测试来自 2 个重新利用的文库的 1600 多种化合物拯救这些细胞生长缺陷的能力。在确定的阳性结果中，我们选择了广谱抗菌分子 nifuroxazide。我们表明 nifuroxazide 可以挽救 CHCHD10S59L/+ 患者成纤维细胞中的线粒体网络碎片化和嵴异常。该分子还减少了人 CHCHD10S59L/+ iPSC 衍生的运动神经元的 caspase 依赖性死亡。其益处涉及 KIF5B 介导的线粒体转运增强，患者来源的运动神经元中轴突运动增加和 syntaphilin 降解证明了这一点。我们的研究结果加强了 MICOS-线粒体运输联系。硝呋嗪和类似物是 MICOS 相关疾病（如运动神经元疾病）的潜在治疗方法。它对 syntaphilin 的影响暗示了硝呋嗪在神经系统疾病中的更广泛适用性。