Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase.
10.1016/j.apsb.2022.06.013
- Author:
Xiaoqing ZHOU
1
;
Shaoyang ZHAO
1
;
Tingting LIU
1
;
Lu YAO
1
;
Meimei ZHAO
1
;
Xiaoming YE
1
;
Xiaowen ZHANG
1
;
Qiang GUO
1
;
Pengfei TU
1
;
Kewu ZENG
1
Author Information
1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
- Publication Type:Journal Article
- Keywords:
AGEs;
ATP6V0D1;
Advanced glycation end-products;
Allosteric regulation;
Diabetic neuropathy;
Lysosomal acidification;
Schisandrol A;
Targets;
V-ATPase
- From:
Acta Pharmaceutica Sinica B
2022;12(10):3843-3860
- CountryChina
- Language:English
-
Abstract:
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 acidification. Interestingly, 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.
