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
  • 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.
Products