{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:42:17Z","timestamp":1772779337988,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIH R01 HL157151"],"award-info":[{"award-number":["NIH R01 HL157151"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T\u00dcB\u0130TAK SBAG 121S487"],"award-info":[{"award-number":["T\u00dcB\u0130TAK SBAG 121S487"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In cardiac pathologies, levels of G protein-coupled receptor kinase 2 (GRK2)\u2014which is involved in receptor desensitization and internalization\u2014are elevated. Beyond these receptor-mediated effects, GRK2 also localizes to mitochondria, where it contributes to pathology. GRK2\u2019s activity can be inhibited via S-nitrosylation at Cysteine 340, a post-translational modification mediated by both endogenous and exogenous nitric oxide. Thus, S-nitrosylation is considered as an endogenous brake on GRK2\u2019s catalytic activity, counteracting its hyperactivity observed in disease states. However, it remains unclear whether S-nitrosylation also regulates GRK2\u2019s influence on mitochondrial function. This study aims to investigate how S-nitrosylation regulates mitochondrial localization and function of GRK2 under hypoxia\/reoxygenation stress. To prevent S-nitrosylation at Cys340, we infected AC16 cardiac cells with adenoviruses carrying a GRK2 C340S (Ser) mutation. Our results indicate that inhibiting S-nitrosylation enhances mitochondrial localization of GRK2, especially in response to pathological stimuli. Additionally, mitochondrial function was impaired, as measured by oxygen consumption rates at ATP production. Furthermore, alterations in mitochondrial dynamics and mitophagy led to adverse outcomes when GRK2 was not subject to S-nitrosylation, presumably due to increased catalytic activity. Our findings underscore the importance of GRK2 regulation in cardiac pathologies and suggest that targeting GRK2 or its post-translational modifications may provide therapeutic benefits.<\/jats:p>","DOI":"10.3390\/cells15050458","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:01:07Z","timestamp":1772636467000},"page":"458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cys340Ser Mutation Abolishing S-Nitrosylation Drives GRK2 Mitochondrial Localization and Dysfunction"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-9438","authenticated-orcid":false,"given":"Gizem","family":"Kayki Mutlu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Ankara University, Tandogan, 06100 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0293-5646","authenticated-orcid":false,"given":"Stephanie M.","family":"Kereliuk","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Hoteit","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Kurt","family":"Chuprun","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umur","family":"Mendes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Ankara University, Tandogan, 06100 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3226-7450","authenticated-orcid":false,"given":"Yusuf","family":"Olgar","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Ankara University, 06620 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter J.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"},{"name":"Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cannavo, A., Liccardo, D., and Koch, W.J. 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