Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Bioorg Med Chem. 2019 Jun 15;27(12):2444-2448. doi: 10.1016/j.bmc.2019.02.028. Epub 2019 Feb 16.
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.
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的稳态。在营养物质匮乏时，这个分解代谢过程为细胞提供了必需的基本构建块。细胞代谢，特别是线粒体呼吸，对自噬通量有显著影响，而复合物 I 的功能对于最大程度的自噬是必需的。在帕金森病中，线粒体功能经常受到损害，自噬通量也会发生改变。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，需要新型的工具化合物。在此，我们报告了一种使用高通量筛选方法发现的结构新颖的自噬抑制剂（Authipyrin）。通过靶标鉴定和验证，发现 Authipyrin 直接靶向线粒体复合物 I，从而导致线粒体呼吸和自噬的强烈抑制。
