MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease
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. Mechanisticall...
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| Veröffentlicht in: | Nature Cardiovascular Research 2023-08, Vol.2 (8), p.778-792 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1038/s44161-023-00314-x |
| format | Article |
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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.</description><identifier>ISSN: 2731-0590</identifier><identifier>EISSN: 2731-0590</identifier><identifier>DOI: 10.1038/s44161-023-00314-x</identifier><identifier>PMID: 39195969</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Disease Models, Animal ; Female ; Humans ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Minichromosome Maintenance Proteins - genetics ; Minichromosome Maintenance Proteins - metabolism ; Mitophagy ; Mucocutaneous Lymph Node Syndrome - genetics ; Mucocutaneous Lymph Node Syndrome - metabolism ; Mucocutaneous Lymph Node Syndrome - pathology ; Nitric Oxide - metabolism ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; Signal Transduction ; Ubiquitination</subject><ispartof>Nature Cardiovascular Research, 2023-08, Vol.2 (8), p.778-792</ispartof><rights>2023. The Author(s), under exclusive licence to Springer Nature Limited.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c303t-99c7c35a4139d82295e34ac009882a50e179eb955447b42050b40056bba3bcf63</citedby><cites>FETCH-LOGICAL-c303t-99c7c35a4139d82295e34ac009882a50e179eb955447b42050b40056bba3bcf63</cites><orcidid>0000-0002-9558-4226 ; 0000-0003-2515-5589 ; 0000-0001-5324-2896 ; 0000-0002-0445-4072 ; 0000-0001-6119-8936 ; 0000-0002-2728-2859 ; 0000-0002-2489-4702 ; 0000-0002-3191-6746 ; 0000-0003-1900-0249 ; 0000-0002-8634-0967 ; 0000-0002-2505-0675 ; 0000-0002-4549-1697 ; 0000-0002-4049-0214 ; 0000-0002-8000-3708 ; 0000-0003-2715-0925</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39195969$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Meng</creatorcontrib><creatorcontrib>Xian, Huifang</creatorcontrib><creatorcontrib>Chen, Zhanghua</creatorcontrib><creatorcontrib>Wang, Shang</creatorcontrib><creatorcontrib>Liu, Ming</creatorcontrib><creatorcontrib>Liang, Weiwei</creatorcontrib><creatorcontrib>Tang, Qin</creatorcontrib><creatorcontrib>Liu, Yao</creatorcontrib><creatorcontrib>Huang, Wanming</creatorcontrib><creatorcontrib>Che, Di</creatorcontrib><creatorcontrib>Guo, Caiqin</creatorcontrib><creatorcontrib>Idiiatullina, Elina</creatorcontrib><creatorcontrib>Fang, Rongli</creatorcontrib><creatorcontrib>Al-Azab, Mahmoud</creatorcontrib><creatorcontrib>Chang, Jingjie</creatorcontrib><creatorcontrib>Wang, Rongze</creatorcontrib><creatorcontrib>Li, Xiaojun</creatorcontrib><creatorcontrib>Zuo, Xiaoyu</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Zhao, Jincun</creatorcontrib><creatorcontrib>Tang, Yaping</creatorcontrib><creatorcontrib>Jin, Shouheng</creatorcontrib><creatorcontrib>He, Zhengjie</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><creatorcontrib>Lu, Liwei</creatorcontrib><creatorcontrib>Zhang, Kang</creatorcontrib><creatorcontrib>Wu, Yan</creatorcontrib><creatorcontrib>Bai, Fan</creatorcontrib><creatorcontrib>Lew, Andrew M</creatorcontrib><creatorcontrib>Cui, Jun</creatorcontrib><creatorcontrib>Wu, Yuzhang</creatorcontrib><creatorcontrib>Gu, Xiaoqiong</creatorcontrib><creatorcontrib>Zhang, Yuxia</creatorcontrib><title>MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease</title><title>Nature Cardiovascular Research</title><addtitle>Nat Cardiovasc Res</addtitle><description>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.</description><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Minichromosome Maintenance Proteins - genetics</subject><subject>Minichromosome Maintenance Proteins - metabolism</subject><subject>Mitophagy</subject><subject>Mucocutaneous Lymph Node Syndrome - genetics</subject><subject>Mucocutaneous Lymph Node Syndrome - metabolism</subject><subject>Mucocutaneous Lymph Node Syndrome - pathology</subject><subject>Nitric Oxide - metabolism</subject><subject>Nucleotidyltransferases - genetics</subject><subject>Nucleotidyltransferases - metabolism</subject><subject>Signal Transduction</subject><subject>Ubiquitination</subject><issn>2731-0590</issn><issn>2731-0590</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkE1v1DAQhq0K1Falf4BD5SOXlLHHTuIjWvFR0aoXOFsTZ3bXahIvsRe26p8nZQviNKPR845mHiHeKrhWgO37bIyqVQUaKwBUpjqciHPd4DKyDl7915-Jy5xjB6bWrW2wORVn6JSzrnbn4uludddWI_eRCvdyjCXttrR5lLs5FQ4ly5-Uw36gWW6ZhrKVcZIz512aMsuS5BTLHINMh9izzHEz0RCnzTNFckz7BRpTz4NMa_mVflGmhyj7mJkyvxGv1zRkvnypF-L7p4_fVl-q2_vPN6sPt1VAwFI5F5qAloxC17daO8toKAC4ttVkgVXjuHPWGtN0RoOFzgDYuusIu7Cu8UK8O-5dfvqx51z8GHPgYaCJlws9gmtaa1DjguojGuaU88xrv5vjSPOjV-Cfvfujd79493-8-8MSunrZv-8Wk_8ify3jbyuNfsw</recordid><startdate>20230801</startdate><enddate>20230801</enddate><creator>Lin, Meng</creator><creator>Xian, Huifang</creator><creator>Chen, Zhanghua</creator><creator>Wang, Shang</creator><creator>Liu, Ming</creator><creator>Liang, Weiwei</creator><creator>Tang, Qin</creator><creator>Liu, Yao</creator><creator>Huang, Wanming</creator><creator>Che, Di</creator><creator>Guo, Caiqin</creator><creator>Idiiatullina, Elina</creator><creator>Fang, Rongli</creator><creator>Al-Azab, Mahmoud</creator><creator>Chang, Jingjie</creator><creator>Wang, Rongze</creator><creator>Li, Xiaojun</creator><creator>Zuo, Xiaoyu</creator><creator>Zhang, Yan</creator><creator>Zhao, Jincun</creator><creator>Tang, Yaping</creator><creator>Jin, Shouheng</creator><creator>He, Zhengjie</creator><creator>Feng, Du</creator><creator>Lu, Liwei</creator><creator>Zhang, Kang</creator><creator>Wu, Yan</creator><creator>Bai, Fan</creator><creator>Lew, Andrew M</creator><creator>Cui, Jun</creator><creator>Wu, Yuzhang</creator><creator>Gu, Xiaoqiong</creator><creator>Zhang, Yuxia</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9558-4226</orcidid><orcidid>https://orcid.org/0000-0003-2515-5589</orcidid><orcidid>https://orcid.org/0000-0001-5324-2896</orcidid><orcidid>https://orcid.org/0000-0002-0445-4072</orcidid><orcidid>https://orcid.org/0000-0001-6119-8936</orcidid><orcidid>https://orcid.org/0000-0002-2728-2859</orcidid><orcidid>https://orcid.org/0000-0002-2489-4702</orcidid><orcidid>https://orcid.org/0000-0002-3191-6746</orcidid><orcidid>https://orcid.org/0000-0003-1900-0249</orcidid><orcidid>https://orcid.org/0000-0002-8634-0967</orcidid><orcidid>https://orcid.org/0000-0002-2505-0675</orcidid><orcidid>https://orcid.org/0000-0002-4549-1697</orcidid><orcidid>https://orcid.org/0000-0002-4049-0214</orcidid><orcidid>https://orcid.org/0000-0002-8000-3708</orcidid><orcidid>https://orcid.org/0000-0003-2715-0925</orcidid></search><sort><creationdate>20230801</creationdate><title>MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease</title><author>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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c303t-99c7c35a4139d82295e34ac009882a50e179eb955447b42050b40056bba3bcf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Minichromosome Maintenance Proteins - genetics</topic><topic>Minichromosome Maintenance Proteins - metabolism</topic><topic>Mitophagy</topic><topic>Mucocutaneous Lymph Node Syndrome - genetics</topic><topic>Mucocutaneous Lymph Node Syndrome - metabolism</topic><topic>Mucocutaneous Lymph Node Syndrome - pathology</topic><topic>Nitric Oxide - metabolism</topic><topic>Nucleotidyltransferases - genetics</topic><topic>Nucleotidyltransferases - metabolism</topic><topic>Signal Transduction</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Meng</creatorcontrib><creatorcontrib>Xian, Huifang</creatorcontrib><creatorcontrib>Chen, Zhanghua</creatorcontrib><creatorcontrib>Wang, Shang</creatorcontrib><creatorcontrib>Liu, Ming</creatorcontrib><creatorcontrib>Liang, Weiwei</creatorcontrib><creatorcontrib>Tang, Qin</creatorcontrib><creatorcontrib>Liu, Yao</creatorcontrib><creatorcontrib>Huang, Wanming</creatorcontrib><creatorcontrib>Che, Di</creatorcontrib><creatorcontrib>Guo, Caiqin</creatorcontrib><creatorcontrib>Idiiatullina, Elina</creatorcontrib><creatorcontrib>Fang, Rongli</creatorcontrib><creatorcontrib>Al-Azab, Mahmoud</creatorcontrib><creatorcontrib>Chang, Jingjie</creatorcontrib><creatorcontrib>Wang, Rongze</creatorcontrib><creatorcontrib>Li, Xiaojun</creatorcontrib><creatorcontrib>Zuo, Xiaoyu</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Zhao, Jincun</creatorcontrib><creatorcontrib>Tang, Yaping</creatorcontrib><creatorcontrib>Jin, Shouheng</creatorcontrib><creatorcontrib>He, Zhengjie</creatorcontrib><creatorcontrib>Feng, Du</creatorcontrib><creatorcontrib>Lu, Liwei</creatorcontrib><creatorcontrib>Zhang, Kang</creatorcontrib><creatorcontrib>Wu, Yan</creatorcontrib><creatorcontrib>Bai, Fan</creatorcontrib><creatorcontrib>Lew, Andrew M</creatorcontrib><creatorcontrib>Cui, Jun</creatorcontrib><creatorcontrib>Wu, Yuzhang</creatorcontrib><creatorcontrib>Gu, Xiaoqiong</creatorcontrib><creatorcontrib>Zhang, Yuxia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Nature Cardiovascular Research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Meng</au><au>Xian, Huifang</au><au>Chen, Zhanghua</au><au>Wang, Shang</au><au>Liu, Ming</au><au>Liang, Weiwei</au><au>Tang, Qin</au><au>Liu, Yao</au><au>Huang, Wanming</au><au>Che, Di</au><au>Guo, Caiqin</au><au>Idiiatullina, Elina</au><au>Fang, Rongli</au><au>Al-Azab, Mahmoud</au><au>Chang, Jingjie</au><au>Wang, Rongze</au><au>Li, Xiaojun</au><au>Zuo, Xiaoyu</au><au>Zhang, Yan</au><au>Zhao, Jincun</au><au>Tang, Yaping</au><au>Jin, Shouheng</au><au>He, Zhengjie</au><au>Feng, Du</au><au>Lu, Liwei</au><au>Zhang, Kang</au><au>Wu, Yan</au><au>Bai, Fan</au><au>Lew, Andrew M</au><au>Cui, Jun</au><au>Wu, Yuzhang</au><au>Gu, Xiaoqiong</au><au>Zhang, Yuxia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease</atitle><jtitle>Nature Cardiovascular Research</jtitle><addtitle>Nat Cardiovasc Res</addtitle><date>2023-08-01</date><risdate>2023</risdate><volume>2</volume><issue>8</issue><spage>778</spage><epage>792</epage><pages>778-792</pages><issn>2731-0590</issn><eissn>2731-0590</eissn><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. 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| ispartof | Nature Cardiovascular Research, 2023-08, Vol.2 (8), p.778-792 |
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| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animals Disease Models, Animal Female Humans Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Minichromosome Maintenance Proteins - genetics Minichromosome Maintenance Proteins - metabolism Mitophagy Mucocutaneous Lymph Node Syndrome - genetics Mucocutaneous Lymph Node Syndrome - metabolism Mucocutaneous Lymph Node Syndrome - pathology Nitric Oxide - metabolism Nucleotidyltransferases - genetics Nucleotidyltransferases - metabolism Signal Transduction Ubiquitination |
| title | MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease |
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