Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity  

作　　者：Ke-Wu Zeng Jing-Kang Wang Li-Chao Wang Qiang Guo Ting-Ting Liu Fu-Jiang Wang Na Feng Xiao-Wen Zhang Li-Xi Liao Mei-Mei Zhao Dan Liu Yong Jiang Pengfei Tu 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [2]Proteomics Laboratory,Medical and Healthy Analytical Center,Peking University Health Science Center,Beijing 100191,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第3期975-987,共13页信号转导与靶向治疗（英文）

基　　金：supported by grants from the Natural Science Foundation of China(no.81773932);the National Key R&D Project of China(nos.2019YFC1711000,2019YFC1708902,and 2017YFC1702400).

摘　　要：Mitochondrial fusion/hission dynamics plays a fundamental role in neuroprotection;however,there is till a severe lack oftherapeutic targets for this biological process.Here,we found that the naturally derived small molecule echinacoside(ECH)signifhcantly promotes mitochondrial fusion progression.ECH selectively binds to the previously uncharacterized casein kinase 2(CK2)α'subunit(CK2a)as a direct cellular target,and genetic knockdown of CK2α'abolishes ECH-mediated mitochondrial fusion.Mechanistically,ECH allosterically regulates CK2α'conformation to recruit basic transcription factor 3(BTF 3)to form a binary proteincomplex.Then,the CK2α'/BTF3 complex facilitatesβ-catenin nuclear translocation to activate TCF/AEF transcription factors andstimulate transcription of the mitochondrial fusion gene Mfn2.trikingly,in a mouse middle cerebral artery occlusion(MCAO)model,ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2expression in wild-type but not CK2α'^(+/-)mice.Taken together,our findings reveal,for the first time,that CK2 is essential forpromoting mitochondrial fusion in a Wnt/B-catenin-dependent manner and suggest that pharmacologically targeting CK2 is apromising therapeutic strategy for ischemic stroke.

关 键 词：INJURIES CEREBRAL Small 

分 类 号：R914[医药卫生—药物化学]