Journal article
Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice
Antioxidants, Vol.12(5), p.1001
04/26/2023
DOI: 10.3390/antiox12051001
PMCID: PMC10215409
PMID: 37237867
Abstract
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.
Details
- Title: Subtitle
- Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice
- Creators
- Biyi Chen - University of IowaNastaran Daneshgar - University of IowaHsiang-Chun Lee - Kaohsiung Medical UniversityLong-Sheng Song - University of IowaDao-Fu Dai
- Resource Type
- Journal article
- Publication Details
- Antioxidants, Vol.12(5), p.1001
- DOI
- 10.3390/antiox12051001
- PMID
- 37237867
- PMCID
- PMC10215409
- NLM abbreviation
- Antioxidants (Basel)
- ISSN
- 2076-3921
- eISSN
- 2076-3921
- Grant note
- name: National Institutes of Health, award: HL145138, DK133118, AHA #858512; name: Leigh Syndrome International Consortium, award: NIH HL130346, HL157741, HL157781
- Language
- English
- Date published
- 04/26/2023
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984410797202771
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