Modulation of autophagy by the novel mitochondrial complex I inhibitor Authipyrin
Modulation of autophagy by the novel mitochondrial complex I inhibitor Authipyrin
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DOI：
10.1016/j.bmc.2019.02.028
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发表时间：
2019-06-15
影响因子：
3.5
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
--
作者：
Kaiser, Nadine;Corkery, Dale;Waldmann, Herbert
自噬通过降解长寿命蛋白质、受损细胞器和病原体来确保细胞内稳态。这种分解代谢过程在营养缺乏时提供必要的细胞构建模块。细胞代谢，尤其是线粒体呼吸，对自噬通量有显着影响，而最大化自噬需要复合物I功能。在帕金森病中，线粒体功能经常受损，自噬通量改变。因此，功能失调的细胞器和蛋白质聚集体积累并导致细胞损伤。为了研究线粒体功能和自噬之间的相互依赖性，需要新的工具化合物。在此，我们报告了一种结构新颖的自噬抑制剂（Authipyrin）的发现，使用高内容筛选方法。靶点鉴定和验证导致发现Authipyrin直接靶向线粒体复合物I，从而有效抑制线粒体呼吸以及自噬。
Autophagy ensures cellular homeostasis by the degradation of long-lived proteins, damaged organelles and pathogens. This catabolic process provides essential cellular building blocks upon nutrient deprivation. Cellular metabolism, especially mitochondrial respiration, has a significant influence on autophagic flux, and complex I function is required for maximal autophagy. In Parkinson's disease mitochondrial function is frequently impaired and autophagic flux is altered. Thus, dysfunctional organelles and protein aggregates accumulate and cause cellular damage. In order to investigate the interdependency between mitochondrial function and autophagy, novel tool compounds are required. Herein, we report the discovery of a structurally novel autophagy inhibitor (Authipyrin) using a high content screening approach. Target identification and validation led to the discovery that Authipyrin targets mitochondrial complex I directly, leading to the potent inhibition of mitochondrial respiration as well as autophagy.