Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1-42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

中文翻译：

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基于神经元的高含量测定和CNS活性线粒体治疗药物的筛选。

线粒体动力学和功能受损是许多神经系统疾病和精神疾病的标志，但是尚未报道使用神经元直接筛查线粒体治疗药物的报道。我们开发了使用初级神经元的多元和高含量筛选试验，并确定了67种小分子神经元调节剂（MnMs）的调节剂。多数增加线粒体含量，长度和/或健康状况的MnMs都可增加线粒体功能，而不会改变神经突的生长。MnMs的一个子集可保护原代神经元的线粒体免受Aβ（1-42）毒性，谷氨酸毒性和氧化应激的增加。某些MnMs可以直接靶向线粒体。最高的MnM还增加了海马神经元的突触活性，并被证明在体内有效，给小鼠服用该化合物后，增加了脑线粒体的呼吸速率。我们的结果提供了一个平台，可直接查询神经元中的转移过程，线粒体动力学和功能的小分子调节剂的集合以及线粒体治疗的候选分子。