Disruption of Sarcoplasmic Reticulum Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2

Jin Li, Xi Qi, Kennedy S. Ramos, Eva Lanters, Jaap Keijer, Natasja de Groot, Bianca Brundel, Deli Zhang

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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 tachypacingand 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.
Original languageEnglish
Article numbere024478
JournalJournal of the American Heart Association
Issue number19
Publication statusPublished - 4 Oct 2022


  • Drosophila
  • atrial fibrillation
  • diabetes
  • microtubules
  • mitosusin 2
  • sarcoplasmic reticulum-mitochondrial contacts

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