دورية أكاديمية
Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling
| العنوان: | Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling |
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| المؤلفون: | Santin, Yohan, Fazal, Loubina, Sainte-Marie, Yannis, Sicard, Pierre, Maggiorani, Damien, Tortosa, Florence, Yücel, Yasemin Yücel, Teyssedre, Lise, Rouquette, Jacques, Marcellin, Marlène, Vindis, Cecile, C., Shih, Jean, Lairez, Olivier, Burlet-Schiltz, Odile, Parini, Angelo, Lezoualc’h, Frank, Mialet-Perez, Jeanne |
| المساهمون: | Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Biochemistry Istanbul, Turkey (School of Pharmacy), Altinbas University Istanbul, Turkey, Institut des Technologies Avancées en sciences du Vivant (ITAV), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), University of Southern California (USC), This work was supported by grants from Agence Nationale pour la Recherche referenced as “ANRJCJC CARDIOMAO”, “ProFIANR-10-INBS-08”, “ANR-17-CE14-0014-01”, grants from European funds (FEDER), Fondazione Cariplo (2014-0672), Fondation pour la Recherche Médicale (équipe FRM2016, DEQ20160334892) and Région Occitanie., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-CE14-0014,EPACK,EPAC1 : Une nouvelle cible thérapeutique dans les maladies rénales chroniques(2017) |
| المصدر: | ISSN: 1350-9047. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2020 |
| المجموعة: | Université Toulouse III - Paul Sabatier: HAL-UPS |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system |
| الوصف: | International audience ; Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa2+ mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/31819159; inserm-02445983; https://inserm.hal.science/inserm-02445983Test; https://inserm.hal.science/inserm-02445983/documentTest; https://inserm.hal.science/inserm-02445983/file/Final-CDD%202019-Santin.pdfTest; PUBMED: 31819159 |
| DOI: | 10.1038/s41418-019-0470-y |
| الإتاحة: | https://doi.org/10.1038/s41418-019-0470-yTest https://inserm.hal.science/inserm-02445983Test https://inserm.hal.science/inserm-02445983/documentTest https://inserm.hal.science/inserm-02445983/file/Final-CDD%202019-Santin.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.4E1F568D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41418-019-0470-y |
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