Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition.
Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition.
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DOI：
10.1038/srep05896
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发表时间：
2014-07-31
影响因子：
4.6
通讯作者：
Sakai Y
中科院分区：
文献类型：
--
作者：
Maharjan S;Oku M;Tsuda M;Hoseki J;Sakai Y
线粒体和泛素蛋白酶体系统的功能障碍以及活性氧 (ROS) 的产生与许多与衰老相关的神经退行性疾病有关。然而，这些事件的顺序仍不清楚。在这里，我们表明，在蛋白酶体抑制下，线粒体发生了最初的损伤。荧光氧化还原探针测量表明，蛋白酶体抑制导致线粒体氧化，随后发生胞质氧化，这可以通过线粒体靶向的抗氧化剂或抗氧化酶来预防。这些观察结果表明，蛋白酶体功能障碍会导致线粒体损伤，导致线粒体增加 ROS 产生并导致细胞质氧化。此外，食物中发现的几种抗氧化剂可以通过维持线粒体膜电位和减少线粒体活性氧的产生来防止细胞内氧化并提高细胞存活率。然而，这些抗氧化剂治疗并没有减少因蛋白酶体抑制而引起的蛋白质聚集体的积累。这些结果表明线粒体的抗氧化保护维持了细胞完整性，为蛋白酶体功能障碍引起的细胞死亡机制提供了新的见解。
Dysfunctions of the mitochondria and the ubiquitin–proteasome system, as well as generation of reactive oxygen species (ROS), are linked to many aging-related neurodegenerative disorders. However, the order of these events remains unclear. Here, we show that the initial impairment occurs in mitochondria under proteasome inhibition. Fluorescent redox probe measurements revealed that proteasome inhibition led to mitochondrial oxidation followed by cytosolic oxidation, which could be prevented by a mitochondrial-targeted antioxidant or antioxidative enzyme. These observations demonstrated that proteasome dysfunction causes damage to mitochondria, leading them to increase their ROS production and resulting in cytosolic oxidation. Moreover, several antioxidants found in foods prevented intracellular oxidation and improved cell survival by maintaining mitochondrial membrane potential and reducing mitochondrial ROS generation. However, these antioxidant treatments did not decrease the accumulation of protein aggregates caused by inhibition of the proteasome. These results suggested that antioxidative protection of mitochondria maintains cellular integrity, providing novel insights into the mechanisms of cell death caused by proteasome dysfunction.
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