Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity
Abstract Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusio...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-02-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-020-00447-6 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ke-Wu Zeng |
| collection | DOAJ |
| description | Abstract Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) 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 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke. |
| format | Article |
| id | doaj-art-72bc1769597745a39d0d9860b2d08daa |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2021-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-72bc1769597745a39d0d9860b2d08daa2025-08-20T01:56:09ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352021-02-016111310.1038/s41392-020-00447-6Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activityKe-Wu Zeng0Jing-Kang Wang1Li-Chao Wang2Qiang Guo3Ting-Ting Liu4Fu-Jiang Wang5Na Feng6Xiao-Wen Zhang7Li-Xi Liao8Mei-Mei Zhao9Dan Liu10Yong Jiang11Pengfei Tu12State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityProteomics Laboratory, Medical and Healthy Analytical Center, Peking University Health Science CenterState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityAbstract Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) 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 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.https://doi.org/10.1038/s41392-020-00447-6 |
| spellingShingle | 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 Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity Signal Transduction and Targeted Therapy |
| title | Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity |
| title_full | Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity |
| title_fullStr | Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity |
| title_full_unstemmed | Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity |
| title_short | Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity |
| title_sort | small molecule induces mitochondrial fusion for neuroprotection via targeting ck2 without affecting its conventional kinase activity |
| url | https://doi.org/10.1038/s41392-020-00447-6 |
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