Disruption of Sarcoplasmic ReticulumMitochondrial 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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Abstract

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
Volume11
Issue number19
DOIs
Publication statusPublished - 4 Oct 2022

Bibliographical note

Funding Information:
This work was supported by the Dutch Heart Foundation (2017T029, 2013T144, 2013T096), Dutch Heart Foundation and Dutch Research Council NWO (CVON-STW2016-14728), The Dutch Research Council NWO ZonMw VENI (09150161910179), The AFIP Foundation, and Medical Delta.

Publisher Copyright:
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

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