Phosphorylation in Novel Mitochondrial Creatine Kinase Tyrosine Residues Render Cardioprotection against Hypoxia/Reoxygenation Injury
| العنوان: | Phosphorylation in Novel Mitochondrial Creatine Kinase Tyrosine Residues Render Cardioprotection against Hypoxia/Reoxygenation Injury |
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| المؤلفون: | Ippei Shimizu, Nammi Park, Jubert Marquez, Maria Victoria Faith Garcia, Sung Ryul Lee, Jin Han, Hyoung Kyu Kim |
| المصدر: | Journal of Lipid and Atherosclerosis |
| بيانات النشر: | Korean Society of Lipidology and Atherosclerosis, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cardioprotection, Endocrinology, Diabetes and Metabolism, Mitochondrion, Cell biology, Mitochondria, Dephosphorylation, chemistry.chemical_compound, chemistry, Reoxygenation, Internal Medicine, Phosphorylation, Ischemic preconditioning, Original Article, Viability assay, CKMT2, Cardiology and Cardiovascular Medicine, Creatine kinase, mitochondrial form, Hypoxia, Adenosine triphosphate |
| الوصف: | Objective Ischemic cardiomyopathy (ICM) is the leading cause of heart failure. Proteomic and genomic studies have demonstrated ischemic preconditioning (IPC) can assert cardioprotection against ICM through mitochondrial function regulation. Considering IPC is conducted in a relatively brief period, regulation of protein expression also occurs very rapidly, highlighting the importance of protein function modulation by post-translational modifications. This study aimed to identify and analyze novel phosphorylated mitochondrial proteins that can be harnessed for therapeutic strategies for preventing ischemia/reperfusion (I/R) injury. Methods Sprague-Dawley rat hearts were used in an ex vivo Langendorff system to simulate normal perfusion, I/R, and IPC condition, after which the samples were prepared for phosphoproteomic analysis. Employing human cardiomyocyte AC16 cells, we investigated the cardioprotective role of CKMT2 through overexpression and how site-directed mutagenesis of putative CKMT2 phosphorylation sites (Y159A, Y255A, and Y368A) can affect cardioprotection by measuring CKMT2 protein activity, mitochondrial function and protein expression changes. Results The phosphoproteomic analysis revealed dephosphorylation of mitochondrial creatine kinase (CKMT2) during ischemia and I/R, while preserving its phosphorylated state during IPC. CKMT2 overexpression conferred cardioprotection against hypoxia/reoxygenation (H/R) by increasing cell viability and mitochondrial adenosine triphosphate level, preserving mitochondrial membrane potential, and reduced reactive oxygen species (ROS) generation, while phosphomutations, especially in Y368, nullified cardioprotection by significantly reducing cell viability and increasing ROS production during H/R. CKMT2 overexpression increased mitochondrial function by mediating the proliferator-activated receptor γ coactivator-1α/estrogen-related receptor-α pathway, and these effects were mostly inhibited by Y368A mutation. Conclusion These results suggest that regulation of quantitative expression and phosphorylation site Y368 of CKMT2 offers a unique mechanism in future ICM therapeutics. |
| اللغة: | English |
| تدمد: | 2288-2561 2287-2892 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::054910490079a11ee9e14b28309010b9 http://europepmc.org/articles/PMC8159762 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....054910490079a11ee9e14b28309010b9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22882561 22872892 |
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