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

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 iden-tified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conforma-tion 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 cross-talk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mito-chondria l homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidi-fication, and also provide the first small-molecule template allosterically activating V-ATPase for prevent-ing diabetic neuropathy.(c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study discovered a natural small-molecule schisandrol A (SolA) that has a significant protective effect against AGEs-induced neuronal cell apoptosis. SolA targets ATP6V0D1 to regulate lysosomal acidification, thereby preserving mitochondrial homeostasis and promoting neuronal cell survival.