Disruption of sarcoplasmic reticulum-mitochondrial contacts underlies contractile dysfunction in experimental and human atrial fibrillation: a key role of mitofusion 2
Presented by: Deli Zhang
Presentation time:
Background: Atrial fibrillation (AF), the most common tachyarrhythmia, is a progressive cardiac dysfunction. SR-mitochondrial contacts (SRMCs) are necessary for normal cardiomyocyte contraction as they regulate the communication between sarcoplasmic reticulum (SR) and mitochondria controlling the Ca2+ and energy (ATP) homeostasis. Notably, SRMCs are mediated by microtubules. Previously, we discovered a significant decrease of acetyl α-tubulin in AF, which leads to microtubule disruption and AF progression. However, the mechanism by which microtubule disruption leads to AF progression is largely unknown. This study aims to determine whether SRMCs disruption underlies the AF onset/progression.
Methods and Results: Tachypacing and high glucose (HG, mimicking diabetes) were used to induce AF and contractile dysfunction in HL-1 atrial cardiomyocytes and in Drosophila. Contractile dysfunction was observed in both tachypacing- and HG-treated HL-1 cardiomyocytes and Drosophila models for AF, which was inhibited by pretreatment with microtubule stabilizers. Moreover, both tachypacing- and HG- induced a significant reduction of SRMCs and mitofusion 2 (MFN2, a SRMC tether protein), with tachypacing showing more severer reduction. This reduction of SRMCs/MFN2 was prevented by the microtubule stabilizers, which consequently attenuated mitochondrial dysfunction and AF progression. In line with pharmacological interventions, genetic overexpression of MFN2 inhibited tachypacing- and/or HG-induced contractile dysfunction in HL-1 cardiomyocytes and Drosophila. Moreover, cardiac specific knockdown of MFN2 induced contractile dysfunction in Drosophila. Finally, MFN2 was significantly reduced in the atrial tissue of persistent AF patients compared to control patients, which was aggravated by diabetes mellitus (DM).
Conclusions: We discovered loss of SRMCs in experimental and human AF associated with DM. Both pharmacological and genetic preservation of SRMCs attenuates contractile dysfunction in experimental models for AF and HG-induced arrhythmia. Therefore, SRMCs may play a critical role in clinical AF onset and progression and the SRMC tether protein MFN2 represents a novel potential therapeutic target for AF, especially DM-induced AF.
Methods and Results: Tachypacing and high glucose (HG, mimicking diabetes) were used to induce AF and contractile dysfunction in HL-1 atrial cardiomyocytes and in Drosophila. Contractile dysfunction was observed in both tachypacing- and HG-treated HL-1 cardiomyocytes and Drosophila models for AF, which was inhibited by pretreatment with microtubule stabilizers. Moreover, both tachypacing- and HG- induced a significant reduction of SRMCs and mitofusion 2 (MFN2, a SRMC tether protein), with tachypacing showing more severer reduction. This reduction of SRMCs/MFN2 was prevented by the microtubule stabilizers, which consequently attenuated mitochondrial dysfunction and AF progression. In line with pharmacological interventions, genetic overexpression of MFN2 inhibited tachypacing- and/or HG-induced contractile dysfunction in HL-1 cardiomyocytes and Drosophila. Moreover, cardiac specific knockdown of MFN2 induced contractile dysfunction in Drosophila. Finally, MFN2 was significantly reduced in the atrial tissue of persistent AF patients compared to control patients, which was aggravated by diabetes mellitus (DM).
Conclusions: We discovered loss of SRMCs in experimental and human AF associated with DM. Both pharmacological and genetic preservation of SRMCs attenuates contractile dysfunction in experimental models for AF and HG-induced arrhythmia. Therefore, SRMCs may play a critical role in clinical AF onset and progression and the SRMC tether protein MFN2 represents a novel potential therapeutic target for AF, especially DM-induced AF.