iScience (Jul 2022)
Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation
- 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
Affiliations
- Takeshi Tokuyama
- Laboratory 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 author
- Hideki Uosaki
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
- Ayumu Sugiura
- Laboratory 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, Japan
- Gen Nishitai
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
- Keisuke Takeda
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
- Shun Nagashima
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
- Isshin Shiiba
- Laboratory 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
- Naoki Ito
- Laboratory 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
- Taku Amo
- Department of Applied Chemistry, National Defense Academy, Yokosuka, Japan
- Satoshi Mohri
- First Department of Physiology, Kawasaki Medical School, Kurashiki, Japan
- Akiyuki Nishimura
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan
- Motohiro Nishida
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan
- Ayumu Konno
- Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
- Hirokazu Hirai
- Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
- Satoshi Ishido
- Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan
- Takahiro Yoshizawa
- Research Center for Advanced Science and Technology, Shinshu University, Matsumoto, Nagano, Japan
- Takayuki Shindo
- Department 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, Japan
- Shingo Takada
- Department of Lifelong Sport, School of Sports Education, Hokusho University, Ebetsu, Japan
- Shintaro Kinugawa
- Department 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, Japan
- Ryoko Inatome
- Laboratory 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
- Shigeru Yanagi
- Laboratory 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 author
- Journal volume & issue
-
Vol. 25,
no. 7
p. 104582
Abstract
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.
