Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2
Background Atrial fibrillation (AF) is the most common and progressive tachyarrhythmia. Diabetes is a common risk factor for AF. Recent research findings revealed that microtubule network disruption underlies AF. The microtubule network mediates the contact between sarcoplasmic reticulum and mitocho...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.024478 |
| _version_ | 1797857446069272576 |
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| author | Jin Li Xi Qi Kennedy S. Ramos Eva Lanters Jaap Keijer Natasja de Groot Bianca Brundel Deli Zhang |
| author_facet | Jin Li Xi Qi Kennedy S. Ramos Eva Lanters Jaap Keijer Natasja de Groot Bianca Brundel Deli Zhang |
| author_sort | Jin Li |
| collection | DOAJ |
| description | Background Atrial fibrillation (AF) is the most common and progressive tachyarrhythmia. Diabetes is a common risk factor for AF. Recent research findings revealed that microtubule network disruption underlies AF. The microtubule network mediates the contact between sarcoplasmic reticulum and mitochondria, 2 essential organelles for normal cardiomyocyte function. Therefore, disruption of the microtubule network may impair sarcoplasmic reticulum and mitochondrial contacts (SRMCs) and subsequently cardiomyocyte function. The current study aims to determine whether microtubule‐mediated SRMCs disruption underlies diabetes‐associated AF. Methods and Results Tachypacing (mimicking AF) and high glucose (mimicking diabetes) significantly impaired contractile function in HL‐1 cardiomyocytes (loss of calcium transient) and Drosophila (reduced heart rate and increased arrhythmia), both of which were prevented by microtubule stabilizers. Furthermore, both tachypacing and high glucose significantly reduced SRMCs and the key SRMC tether protein mitofusin 2 (MFN2) and resulted in consequent mitochondrial dysfunction, all of which were prevented by microtubule stabilizers. In line with pharmacological interventions with microtubule stabilizers, cardiac‐specific knockdown of MFN2 induced arrhythmia in Drosophila and overexpression of MFN2 prevented tachypacing‐ and high glucose–induced contractile dysfunction in HL‐1 cardiomyocytes and/or Drosophila. Consistently, SRMCs/MFN2 levels were significantly reduced in right atrial appendages of patients with persistent AF compared with control patients, which was aggravated in patients with diabetes. Conclusions SRMCs may play a critical role in clinical AF, especially diabetes‐related AF. Furthermore, SRMCs can be regulated by microtubules and MFN2, which represent novel potential therapeutic targets for AF. |
| first_indexed | 2024-04-09T20:56:50Z |
| format | Article |
| id | doaj.art-cb4959ea7d86455c970c4b1e54c50114 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-09T20:56:50Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-cb4959ea7d86455c970c4b1e54c501142023-03-29T18:35:57ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-10-01111910.1161/JAHA.121.024478Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2Jin Li0Xi Qi1Kennedy S. Ramos2Eva Lanters3Jaap Keijer4Natasja de Groot5Bianca Brundel6Deli Zhang7Department of Physiology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The NetherlandsHuman and Animal Physiology Wageningen University Wageningen The NetherlandsDepartment of Physiology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The NetherlandsDepartment of Cardiology Erasmus Medical Center Rotterdam The NetherlandsHuman and Animal Physiology Wageningen University Wageningen The NetherlandsDepartment of Cardiology Erasmus Medical Center Rotterdam The NetherlandsDepartment of Physiology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The NetherlandsDepartment of Physiology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The NetherlandsBackground Atrial fibrillation (AF) is the most common and progressive tachyarrhythmia. Diabetes is a common risk factor for AF. Recent research findings revealed that microtubule network disruption underlies AF. The microtubule network mediates the contact between sarcoplasmic reticulum and mitochondria, 2 essential organelles for normal cardiomyocyte function. Therefore, disruption of the microtubule network may impair sarcoplasmic reticulum and mitochondrial contacts (SRMCs) and subsequently cardiomyocyte function. The current study aims to determine whether microtubule‐mediated SRMCs disruption underlies diabetes‐associated AF. Methods and Results Tachypacing (mimicking AF) and high glucose (mimicking diabetes) significantly impaired contractile function in HL‐1 cardiomyocytes (loss of calcium transient) and Drosophila (reduced heart rate and increased arrhythmia), both of which were prevented by microtubule stabilizers. Furthermore, both tachypacing and high glucose significantly reduced SRMCs and the key SRMC tether protein mitofusin 2 (MFN2) and resulted in consequent mitochondrial dysfunction, all of which were prevented by microtubule stabilizers. In line with pharmacological interventions with microtubule stabilizers, cardiac‐specific knockdown of MFN2 induced arrhythmia in Drosophila and overexpression of MFN2 prevented tachypacing‐ and high glucose–induced contractile dysfunction in HL‐1 cardiomyocytes and/or Drosophila. Consistently, SRMCs/MFN2 levels were significantly reduced in right atrial appendages of patients with persistent AF compared with control patients, which was aggravated in patients with diabetes. Conclusions SRMCs may play a critical role in clinical AF, especially diabetes‐related AF. Furthermore, SRMCs can be regulated by microtubules and MFN2, which represent novel potential therapeutic targets for AF.https://www.ahajournals.org/doi/10.1161/JAHA.121.024478atrial fibrillationdiabetesDrosophilamicrotubulesmitosusin 2sarcoplasmic reticulum‐mitochondrial contacts |
| spellingShingle | Jin Li Xi Qi Kennedy S. Ramos Eva Lanters Jaap Keijer Natasja de Groot Bianca Brundel Deli Zhang Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atrial fibrillation diabetes Drosophila microtubules mitosusin 2 sarcoplasmic reticulum‐mitochondrial contacts |
| title | Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 |
| title_full | Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 |
| title_fullStr | Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 |
| title_full_unstemmed | Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 |
| title_short | Disruption of Sarcoplasmic Reticulum‐Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2 |
| title_sort | disruption of sarcoplasmic reticulum mitochondrial contacts underlies contractile dysfunction in experimental and human atrial fibrillation a key role of mitofusin 2 |
| topic | atrial fibrillation diabetes Drosophila microtubules mitosusin 2 sarcoplasmic reticulum‐mitochondrial contacts |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.024478 |
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