{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:59:42Z","timestamp":1791233982447,"version":"4.1.0"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81970214 82370266"],"award-info":[{"award-number":["81970214 82370266"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:p>The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, comprises distinct pathways orchestrated by conserved molecular sensors. Although several of these components have been suggested to protect cardiomyocytes from ischemic injury, their precise functions and mechanisms remain elusive. In this study, we observed a marked increase in glucose-regulated protein 94 (GRP94) expression at the border zone of cardiac infarct in a mouse model. GRP94 overexpression ameliorated post-infarction myocardial damage and reduced infarct size. Conversely, GRP94 deficiency exacerbated myocardial dysfunction and infarct size. Mechanistically, GRP94 alleviated hypoxia-induced mitochondrial fragmentation, whereas its depletion exacerbated this fragmentation. Molecular investigations revealed that GRP94 specifically facilitated the cleavage of Opa1 into L-Opa1, but not S-Opa1. The study further elucidated that under hypoxic conditions, the binding shift of Yy1 from lncRNA Oip5os1 to AI662270 promoted Yy1\u2019s binding on the GRP94 promoter, thereby enhancing GRP94 expression. AI662270 attenuated mitochondrial over-fragmentation and ischemic injury after myocardial infarction similarly to GRP94. Moreover, coimmunoprecipitation coupled with LC-MS\/MS identified the interaction of GRP94 with Anxa2, which regulates Akt1 signaling to maintain L-Opa1 levels. Overall, these findings unveiled what we believe is a novel role for the AI662270\/GRP94 axis in linking ER stress to mitochondrial dynamics regulation, proposing new therapeutic avenues for managing cardiovascular conditions through ER stress modulation.<\/jats:p>","DOI":"10.1172\/jci.insight.188904","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T18:17:50Z","timestamp":1759861070000},"source":"Crossref","is-referenced-by-count":5,"title":["AI662270\/GRP94 axis couples the unfolded protein response to mitochondrial dynamics during acute myocardial infarction"],"prefix":"10.1172","volume":"10","author":[{"given":"Suling","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Echocardiography,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Centre, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dili","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Zhu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengshi","family":"Xie","sequence":"additional","affiliation":[{"name":"Wusong Hospital, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Shi","sequence":"additional","affiliation":[{"name":"Wusong Hospital, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,"},{"name":"NHC Key Laboratory of Ischemic Heart Diseases, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Department of Cardiology, The Third People\u2019s Hospital of Huizhou, Huizhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00925-z"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000985"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-125-4-199608150-00009"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(99)00525-7"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00320-3"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.03.025"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2018.08.133"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310266"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-023-01871-z"},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/3462530","article-title":"ER stress activates the NLRP3 inflammasome: a novel mechanism of atherosclerosis","volume":"2019","author":"Chen","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00511-w"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176127"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21931-9"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312641"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.11.006"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.17.2201"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2017.07.019"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.20517\/2574-1209.2022.22"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103049"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2019.05.022"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay2494"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2174-5"},{"key":"B23","first-page":"1","article-title":"Long noncoding RNAs: advances in lipid metabolism","volume":"87","author":"Zeng","year":"2018","journal-title":"Adv Clin Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2480"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0657-7"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.320531"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170104"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adp0443"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0116"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.11.4529-4540.2005"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aao2110"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.008"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103188200"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05678-3"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2289"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15984"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy197"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2017.09.003"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2016.02.010"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.03.003"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1749490"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23020780"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0788-z"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302933110"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26222-x"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2006-0301SM"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-022-02865-0"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2305063"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.055"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000220643.65941.8d"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107682"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2015.1122164"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121983"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1288894"},{"key":"B55","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/978-3-319-48382-5_11","article-title":"Endoplasmic reticulum stress and obesity","volume":"960","author":"Yilmaz","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094843"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32562"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00312-2"},{"key":"B59","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.acr.2015.09.001","article-title":"GRP94\/gp96 in cancer: biology, structure, immunology, and drug development","volume":"129","author":"Wu","year":"2016","journal-title":"Adv Cancer Res"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2011.06.011"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(01)00049-7"},{"key":"B62","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/978-3-030-12457-1_29","article-title":"ER-mitochondria calcium transfer, organelle contacts and neurodegenerative diseases","volume":"1131","author":"Vallese","year":"2020","journal-title":"Adv Exp Med Biol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf5549"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.440453"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309202"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.840"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102098"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1172\/JCI164660"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.009"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0299-0"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0723-6"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/188904\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T15:01:54Z","timestamp":1779030114000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/188904"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":71,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,8,21]]},"published-print":{"date-parts":[[2025,10,8]]}},"alternative-id":["10.1172\/jci.insight.188904"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.188904","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"article-number":"e188904"}}