Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation
Summary: Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquit...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222008549 |
| _version_ | 1818550473243754496 |
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| author | Takeshi Tokuyama Hideki Uosaki Ayumu Sugiura Gen Nishitai Keisuke Takeda Shun Nagashima Isshin Shiiba Naoki Ito Taku Amo Satoshi Mohri Akiyuki Nishimura Motohiro Nishida Ayumu Konno Hirokazu Hirai Satoshi Ishido Takahiro Yoshizawa Takayuki Shindo Shingo Takada Shintaro Kinugawa Ryoko Inatome Shigeru Yanagi |
| author_facet | Takeshi Tokuyama Hideki Uosaki Ayumu Sugiura Gen Nishitai Keisuke Takeda Shun Nagashima Isshin Shiiba Naoki Ito Taku Amo Satoshi Mohri Akiyuki Nishimura Motohiro Nishida Ayumu Konno Hirokazu Hirai Satoshi Ishido Takahiro Yoshizawa Takayuki Shindo Shingo Takada Shintaro Kinugawa Ryoko Inatome Shigeru Yanagi |
| author_sort | Takeshi Tokuyama |
| collection | DOAJ |
| description | Summary: Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquitin ligase MITOL/MARCH5 against cardiac senescence and MI, partly through Drp1 clearance by OMM-associated degradation (OMMAD). Persistent Drp1 accumulation in cardiomyocyte-specific MITOL conditional-knockout mice induced mitochondrial fragmentation and dysfunction, including reduced ATP production and increased ROS generation, ultimately leading to myocardial senescence and chronic heart failure. Furthermore, ischemic stress-induced acute downregulation of MITOL, which permitted mitochondrial accumulation of Drp1, resulted in mitochondrial fragmentation. Adeno-associated virus-mediated delivery of the MITOL gene to cardiomyocytes ameliorated cardiac dysfunction induced by MI. Our findings suggest that OMMAD activation by MITOL can be a therapeutic target for aging-associated heart diseases, including heart failure and MI. |
| first_indexed | 2024-12-12T08:46:56Z |
| format | Article |
| id | doaj.art-eb77f74353bf4977b20163745c270eb9 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-12T08:46:56Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-eb77f74353bf4977b20163745c270eb92022-12-22T00:30:29ZengElsevieriScience2589-00422022-07-01257104582Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulationTakeshi Tokuyama0Hideki Uosaki1Ayumu Sugiura2Gen Nishitai3Keisuke Takeda4Shun Nagashima5Isshin Shiiba6Naoki Ito7Taku Amo8Satoshi Mohri9Akiyuki Nishimura10Motohiro Nishida11Ayumu Konno12Hirokazu Hirai13Satoshi Ishido14Takahiro Yoshizawa15Takayuki Shindo16Shingo Takada17Shintaro Kinugawa18Ryoko Inatome19Shigeru Yanagi20Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Corresponding authorDivision of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Tokyo, JapanDepartment of Applied Chemistry, National Defense Academy, Yokosuka, JapanFirst Department of Physiology, Kawasaki Medical School, Kurashiki, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, JapanDepartment of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, JapanDepartment of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, JapanDepartment of Microbiology, Hyogo College of Medicine, Nishinomiya, JapanResearch Center for Advanced Science and Technology, Shinshu University, Matsumoto, Nagano, JapanDepartment of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Nagano, JapanDepartment of Lifelong Sport, School of Sports Education, Hokusho University, Ebetsu, JapanDepartment of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Tokyo, JapanLaboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Tokyo, Japan; Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Corresponding authorSummary: Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquitin ligase MITOL/MARCH5 against cardiac senescence and MI, partly through Drp1 clearance by OMM-associated degradation (OMMAD). Persistent Drp1 accumulation in cardiomyocyte-specific MITOL conditional-knockout mice induced mitochondrial fragmentation and dysfunction, including reduced ATP production and increased ROS generation, ultimately leading to myocardial senescence and chronic heart failure. Furthermore, ischemic stress-induced acute downregulation of MITOL, which permitted mitochondrial accumulation of Drp1, resulted in mitochondrial fragmentation. Adeno-associated virus-mediated delivery of the MITOL gene to cardiomyocytes ameliorated cardiac dysfunction induced by MI. Our findings suggest that OMMAD activation by MITOL can be a therapeutic target for aging-associated heart diseases, including heart failure and MI.http://www.sciencedirect.com/science/article/pii/S2589004222008549PhysiologyCellular physiologyMolecular biologyDevelopmental biology |
| spellingShingle | Takeshi Tokuyama Hideki Uosaki Ayumu Sugiura Gen Nishitai Keisuke Takeda Shun Nagashima Isshin Shiiba Naoki Ito Taku Amo Satoshi Mohri Akiyuki Nishimura Motohiro Nishida Ayumu Konno Hirokazu Hirai Satoshi Ishido Takahiro Yoshizawa Takayuki Shindo Shingo Takada Shintaro Kinugawa Ryoko Inatome Shigeru Yanagi Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation iScience Physiology Cellular physiology Molecular biology Developmental biology |
| title | Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation |
| title_full | Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation |
| title_fullStr | Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation |
| title_full_unstemmed | Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation |
| title_short | Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation |
| title_sort | protective roles of mitol against myocardial senescence and ischemic injury partly via drp1 regulation |
| topic | Physiology Cellular physiology Molecular biology Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222008549 |
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