The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

中文翻译：

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线粒体输入因子 Mia40 水平的增加阻止了 polyQ 蛋白在细胞质中的聚集

蛋白质聚集体的形成是神经退行性疾病的标志。对患者样本和模型系统的观察表明，聚集体形成与线粒体功能下降之间存在联系，但因果关系尚不清楚。我们使用了酿酒酵母分析线粒体过程如何调节源自人类亨廷顿蛋白的易于聚集的 polyQ 蛋白的行为。Q97-GFP 的表达迅速导致不溶性胞质聚集体和细胞死亡。虽然聚集只是轻微地损害了线粒体呼吸，但它极大地干扰了线粒体前体蛋白的输入。导入成分 Mia40 中的突变体对 Q97-GFP 过敏，而 Mia40 过表达强烈抑制酵母和人类细胞中有毒 Q97-GFP 聚集体的形成。基于这些观察，我们提出线粒体前体蛋白翻译后进入线粒体与易聚集的胞质蛋白竞争分子伴侣和蛋白酶体能力。Mia40 调节这种竞争，因为它在线粒体蛋白质输入中具有限速作用。因此，Mia40 是线粒体生物发生的动态调节器，可用于稳定细胞质蛋白稳态。