Implications of the cardiomyocyte stress response on protein homeostasis in atrial fibrillation

Atrial fibrillation (AF), the most common sustained clinical tachyarrhythmia, is characterized by electrical and structural remodeling. Derailment of proteostasis, the homeostasis of protein production, function and degradation, contributes significantly to AF-induced remodeling. Endoplasmic reticulum (ER) stress was previously found present in AF, which may lead to myolysis. The ER is closely linked to mitochondria and ER stress can result in mitochondrial stress. Importantly, mitochondrial stress is observed in AF pathogenesis. Here, we report that in vitro tachypacing of HL-1 cardiomyocytes induces mitochondrial dysfunction and fragmentation of the mitochondrial network, which was verified in AF patients. Partial blocking or downregulating the mitochondrial calcium uniporter (MCU) precludes mitochondrial dysfunction and mitochondrial fragmentation in tachypaced cardiomyocytes, suggesting that augmented mitochondrial Ca 2+ influx constitutes a key pathophysiological mechanism. Blocking the MCU pharmacologically, by Ru360, also protects against contractile dysfunction in an in vivo Drosophila AF model. In addition, AF patients display increased levels of circulating mitochondrial DNA, indicating mitochondrial DNA may act as a biomarker for AF. Together, these results suggest that inhibition of the MCU may represent a novel therapeutic target to counteract AF-induced mitochondrial dysfunction, and that circulating mitochondrial DNA in serum may represent a biomarker for AF.

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