Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase

作     者：Xiaoqing Zhou Shaoyang Zhao Tingting Liu Lu Yao Meimei Zhao Xiaoming Ye Xiaowen Zhang Qiang Guo Pengfei Tu Kewu Zeng 

作者机构：State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第10期

页      面：3843-3860页

核心收录：

学科分类：1008[医学-中药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by National Key Research and Development Program of China(Nos.2019YFC1708902 and 2019YFC1711000) National Natural Science Foundation of China(Nos.81973505,81773932 and 82104621) 

主　　题：Allosteric regulation Advanced glycation endproducts AGEs Lysosomal acidification Targets V-ATPase ATP6V0D1 Schisandrol A Diabetic neuropathy 

摘      要：Diabetes have been shown to cause progressive neuronal injury with pain and numbness via advanced glycation end-products(AGEs)-induced neuronal cell apoptosis;however, the valuable drug targets for diabetic neuropathy have been poorly reported so far. In this study, we discovered a natural small-molecule schisandrol A(SolA) with significant protective effect against AGEs-induced neuronal cell apoptosis. ATP6V0D1, a major subunit of vacuolar-type ATPase(V-ATPase) in lysosome was identified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conformation via targeting a unique cysteine 335 residue to activate V-ATPase-dependent lysosomal ***, SolA-induced lysosome pH downregulation resulted in a mitochondrial-lysosomal crosstalk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mitochondrial homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidification, and also provide the first small-molecule template allosterically activating V-ATPase for preventing diabetic neuropathy.