2. Academic Validation
  3. Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation

Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation

  • iScience. 2022 Jun 11;25(7):104582. doi: 10.1016/j.isci.2022.104582.
Takeshi Tokuyama 1 2,  Hideki Uosaki 2,  Ayumu Sugiura 1 3,  Gen Nishitai 1,  Keisuke Takeda 1,  Shun Nagashima 1,  Isshin Shiiba 1 4,  Naoki Ito 1 4,  Taku Amo 5,  Satoshi Mohri 6,  Akiyuki Nishimura 7 8,  Motohiro Nishida 7 8,  Ayumu Konno 9,  Hirokazu Hirai 9,  Satoshi Ishido 10,  Takahiro Yoshizawa 11,  Takayuki Shindo 12 13,  Shingo Takada 14,  Shintaro Kinugawa 15 16,  Ryoko Inatome 1 4,  Shigeru Yanagi 1 4 16
Affiliations

Affiliations

  • 1 Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
  • 2 Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
  • 3 Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  • 4 Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Tokyo, Japan.
  • 5 Department of Applied Chemistry, National Defense Academy, Yokosuka, Japan.
  • 6 First Department of Physiology, Kawasaki Medical School, Kurashiki, Japan.
  • 7 Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
  • 8 National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan.
  • 9 Department of Neurophysiology and Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
  • 10 Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan.
  • 11 Research Center for Advanced Science and Technology, Shinshu University, Matsumoto, Nagano, Japan.
  • 12 Department of Cardiovascular Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
  • 13 Department of Life Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Nagano, Japan.
  • 14 Department of Lifelong Sport, School of Sports Education, Hokusho University, Ebetsu, Japan.
  • 15 Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 16 Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
PMID: 35789860 DOI: 10.1016/j.isci.2022.104582
Abstract

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.

Keywords

Cellular physiology; Developmental biology; Molecular biology; Physiology.

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