Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila. We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.

中文翻译：

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线粒体应激通过 ATF4 依赖性 L-2-羟基戊二酸增加导致神经元功能障碍


线粒体应激会导致一系列神经系统疾病。线粒体应激触发的线粒体核信号通路重塑细胞生理和代谢。人们对这些信号传导机制如何导致神经元功能障碍和疾病知之甚少。我们发现神经元中的线粒体应激会激活转录因子 ATF4，作为果蝇内质网未折叠蛋白反应 (UPR) 的一部分。我们发现 ATF4 激活会重新编程核基因表达并导致神经元功能障碍。线粒体应激导致果蝇大脑中代谢物 L-2-羟基戊二酸 (L-2-HG) 水平的 ATF4 依赖性增加。通过过度表达 L-2-HG 脱氢酶，直接降低 L-2-HG 水平，可改善神经功能。因此，通过线粒体应激信号调节 L-2-HG 水平可以调节神经元功能。