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

doi:10.1016/j.isci.2022.104582

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. eCollection 2022 Jul 15.

Authors

Takeshi Tokuyama^{1

2}, Hideki Uosaki², Ayumu Sugiura^{1

3}, Gen Nishitai¹, Keisuke Takeda¹, Shun Nagashima¹, Isshin Shiiba^{1

4}, Naoki Ito^{1

4}, Taku Amo⁵, Satoshi Mohri⁶, Akiyuki Nishimura^{7

8}, Motohiro Nishida^{7

8}, Ayumu Konno⁹, Hirokazu Hirai⁹, Satoshi Ishido¹⁰, Takahiro Yoshizawa¹¹, Takayuki Shindo^{12

13}, Shingo Takada¹⁴, 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.

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.