Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy
Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique e...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1118017/full |
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| author | Ji-Chao Zhou Cai-Cai Jin Xiao-Li Wei Rui-Bing Xu Ruo-Yu Wang Zhi-Meng Zhang Bo Tang Jin-Mei Yu Jiao-Jiao Yu Shuang Shang Xiao-Xi Lv Fang Hua Ping-Ping Li Zhuo-Wei Hu Yong-Mei Shen Feng-Peng Wang Xiu-Ying Ma Xiu-Ying Ma Bing Cui Fu-Neng Geng Xiao-Wei Zhang |
| author_facet | Ji-Chao Zhou Cai-Cai Jin Xiao-Li Wei Rui-Bing Xu Ruo-Yu Wang Zhi-Meng Zhang Bo Tang Jin-Mei Yu Jiao-Jiao Yu Shuang Shang Xiao-Xi Lv Fang Hua Ping-Ping Li Zhuo-Wei Hu Yong-Mei Shen Feng-Peng Wang Xiu-Ying Ma Xiu-Ying Ma Bing Cui Fu-Neng Geng Xiao-Wei Zhang |
| author_sort | Ji-Chao Zhou |
| collection | DOAJ |
| description | Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure. |
| first_indexed | 2024-04-09T18:17:16Z |
| format | Article |
| id | doaj.art-ac2647d0d2cd476885f204369d00439a |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-09T18:17:16Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-ac2647d0d2cd476885f204369d00439a2023-04-12T22:37:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-04-011410.3389/fphar.2023.11180171118017Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagyJi-Chao Zhou0Cai-Cai Jin1Xiao-Li Wei2Rui-Bing Xu3Ruo-Yu Wang4Zhi-Meng Zhang5Bo Tang6Jin-Mei Yu7Jiao-Jiao Yu8Shuang Shang9Xiao-Xi Lv10Fang Hua11Ping-Ping Li12Zhuo-Wei Hu13Yong-Mei Shen14Feng-Peng Wang15Xiu-Ying Ma16Xiu-Ying Ma17Bing Cui18Fu-Neng Geng19Xiao-Wei Zhang20State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaSichuan Engineering Research Center for Medicinal Animals, Sichuan, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaSichuan Engineering Research Center for Medicinal Animals, Sichuan, ChinaDepartment of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, Sichuan, ChinaSichuan Engineering Research Center for Medicinal Animals, Sichuan, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaSichuan Engineering Research Center for Medicinal Animals, Sichuan, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaAberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.https://www.frontiersin.org/articles/10.3389/fphar.2023.1118017/fullAconitum carmichaeliimitochondrial homeostasismyocardial energy metabolismoxidative stress injurySqstm1 |
| spellingShingle | Ji-Chao Zhou Cai-Cai Jin Xiao-Li Wei Rui-Bing Xu Ruo-Yu Wang Zhi-Meng Zhang Bo Tang Jin-Mei Yu Jiao-Jiao Yu Shuang Shang Xiao-Xi Lv Fang Hua Ping-Ping Li Zhuo-Wei Hu Yong-Mei Shen Feng-Peng Wang Xiu-Ying Ma Xiu-Ying Ma Bing Cui Fu-Neng Geng Xiao-Wei Zhang Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy Frontiers in Pharmacology Aconitum carmichaelii mitochondrial homeostasis myocardial energy metabolism oxidative stress injury Sqstm1 |
| title | Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy |
| title_full | Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy |
| title_fullStr | Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy |
| title_full_unstemmed | Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy |
| title_short | Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy |
| title_sort | mesaconine alleviates doxorubicin triggered cardiotoxicity and heart failure by activating pink1 dependent cardiac mitophagy |
| topic | Aconitum carmichaelii mitochondrial homeostasis myocardial energy metabolism oxidative stress injury Sqstm1 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1118017/full |
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