{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T20:13:02Z","timestamp":1778616782612,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["HL145138"],"award-info":[{"award-number":["HL145138"]}]},{"name":"National Institutes of Health","award":["DK133118"],"award-info":[{"award-number":["DK133118"]}]},{"name":"National Institutes of Health","award":["AHA #858512"],"award-info":[{"award-number":["AHA #858512"]}]},{"name":"National Institutes of Health","award":["NIH HL130346"],"award-info":[{"award-number":["NIH HL130346"]}]},{"name":"National Institutes of Health","award":["HL157741"],"award-info":[{"award-number":["HL157741"]}]},{"name":"National Institutes of Health","award":["HL157781"],"award-info":[{"award-number":["HL157781"]}]},{"name":"Leigh Syndrome International Consortium","award":["HL145138"],"award-info":[{"award-number":["HL145138"]}]},{"name":"Leigh Syndrome International Consortium","award":["DK133118"],"award-info":[{"award-number":["DK133118"]}]},{"name":"Leigh Syndrome International Consortium","award":["AHA #858512"],"award-info":[{"award-number":["AHA #858512"]}]},{"name":"Leigh Syndrome International Consortium","award":["NIH HL130346"],"award-info":[{"award-number":["NIH HL130346"]}]},{"name":"Leigh Syndrome International Consortium","award":["HL157741"],"award-info":[{"award-number":["HL157741"]}]},{"name":"Leigh Syndrome International Consortium","award":["HL157781"],"award-info":[{"award-number":["HL157781"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh Syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.<\/jats:p>","DOI":"10.3390\/antiox12051001","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T01:16:25Z","timestamp":1682471785000},"page":"1001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-7537","authenticated-orcid":false,"given":"Biyi","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0703-0494","authenticated-orcid":false,"given":"Nastaran","family":"Daneshgar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5877-9059","authenticated-orcid":false,"given":"Hsiang-Chun","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long-Sheng","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dao-Fu","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1097\/00004872-200018060-00002","article-title":"Role of oxidative stress in cardiovascular diseases","volume":"18","author":"Dhalla","year":"2000","journal-title":"J. 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