MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease

Lin, Meng; Xian, Huifang; Chen, Zhanghua; Wang, Shang; Liu, Ming; Liang, Weiwei; Tang, Qin; Liu, Yao; Huang, Wanming; Che, Di; Guo, Caiqin; Idiiatullina, Elina; Fang, Rongli; Al-Azab, Mahmoud; Chang, Jingjie; Wang, Rongze; Li, Xiaojun; Zuo, Xiaoyu; Zhang, Yan; Zhao, Jincun; Tang, Yaping; Jin, Shouheng; He, Zhengjie; Feng, Du; Lu, Liwei; Zhang, Kang; Wu, Yan; Bai, Fan; Lew, Andrew M; Cui, Jun; Wu, Yuzhang; Gu, Xiaoqiong; Zhang, Yuxia

Author(s): Lin, Meng; Xian, Huifang; Chen, Zhanghua; Wang, Shang; Liu, Ming; Liang, Weiwei; Tang, Qin; Liu, Yao; Huang, Wanming; Che, Di; Guo, Caiqin; Idiiatullina, Elina; Fang, Rongli; Al-Azab, Mahmoud; Chang, Jingjie; Wang, Rongze; Li, Xiaojun; Zuo, Xiaoyu; Zhang, Yan; Zhao, Jincun; Tang, Yaping; Jin, Shouheng; He, Zhengjie; Feng, Du; Lu, Liwei; Zhang, Kang; Wu, Yan; Bai, Fan; Lew, Andrew M; Cui, Jun; Wu, Yuzhang; Gu, Xiaoqiong; Zhang, Yuxia;
Details: Publication Year 2023-08-01,Volume 2,Issue #8,Page 778-792
Journal Title: Nature Cardiovascular Research
Abstract: Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.
Publisher: NPG
Research Division(s): Immunology
Publisher's Version: https://doi.org/10.1038/s44161-023-00314-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-28 09:37:15

Last Modified: 2023-08-28 09:49:36