TY - JOUR
T1 - Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation
AU - Tokuyama, Takeshi
AU - Uosaki, Hideki
AU - Sugiura, Ayumu
AU - Nishitai, Gen
AU - Takeda, Keisuke
AU - Nagashima, Shun
AU - Shiiba, Isshin
AU - Ito, Naoki
AU - Amo, Taku
AU - Mohri, Satoshi
AU - Nishimura, Akiyuki
AU - Nishida, Motohiro
AU - Konno, Ayumu
AU - Hirai, Hirokazu
AU - Ishido, Satoshi
AU - Yoshizawa, Takahiro
AU - Shindo, Takayuki
AU - Takada, Shingo
AU - Kinugawa, Shintaro
AU - Inatome, Ryoko
AU - Yanagi, Shigeru
N1 - Funding Information:
This study was supported in part by MEXT / JSPS KAKENHI (to T.T., R.I., and S.Y.), the Uehara Memorial Foundation and AMED under Grant Number JP17gm5010002 , 18gm5010002 , 19gm5010002 , 20gm5010002 , 21gm5010002 to S.Y.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.isci.2022.104582
DO - 10.1016/j.isci.2022.104582
M3 - Article
AN - SCOPUS:85132872546
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 7
M1 - 104582
ER -