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首页> 外文期刊>Cell metabolism >Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system
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Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system

机译：线粒体/蛋白酶体系统活性的降低可调节人线粒体疾病的发病机理

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Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS formation is largely unknown. Here, we identify a link between mitochondrial stress and ubiquitin-dependent proteolysis, which supports cellular surveillance both in Caenorhabditis elegans and humans. Worms defective in respiration with elevated ROS levels are limited in turnover of a GFP-based substrate protein, demonstrating that mitochondrial stress affects the ubiquitin/proteasome system (UPS). Intriguingly, we observed similar proteolytic defects for disease-causing IVD and COX1 mutations associated with mitochondrial failure in humans. Together, these results identify a conserved link between mitochondrial metabolism and ubiquitin-dependent proteostasis. Reduced UPS activity during pathological conditions might potentiate disease progression and thus provides a valuable target for therapeutic intervention.
机译：线粒体通过协调ATP合成与代谢活性，氧化还原信号传导和凋亡来维持细胞稳态。线粒体来源的活性氧（ROS）含量过高会促进线粒体功能障碍，引发许多代谢异常。但是，对于过量的ROS形成有害作用的分子基础尚不清楚。在这里，我们确定线粒体压力和泛素依赖性蛋白水解之间的联系，这支持秀丽隐杆线虫和人类的细胞监测。 ROS水平升高的呼吸缺陷蠕虫在基于GFP的底物蛋白的更新过程中受到限制，表明线粒体应激影响泛素/蛋白酶体系统（UPS）。有趣的是，我们观察到与人类线粒体衰竭有关的致病性IVD和COX1突变具有类似的蛋白水解缺陷。总之，这些结果确定了线粒体代谢与泛素依赖性蛋白稳态之间的保守联系。病理状态下UPS活动的减少可能会增强疾病的进展，从而为治疗干预提供了有价值的目标。

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