Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Acta Physiol (Oxf). 2014 Feb;210(2):330-41. doi: 10.1111/apha.12162. Epub 2013 Oct 5.
Iron overload in the heart can lead to iron-overload cardiomyopathy and cardiac arrhythmia. In the past decades, growing evidence has suggested that cardiac mitochondrial dysfunction is associated with the development of cardiac dysfunction and lethal arrhythmias. Despite these facts, the effect of iron overload on cardiac mitochondrial function is still unclear. In this study, we determined the effects of iron overload on the cardiac mitochondrial function and the routes of cardiac mitochondrial iron uptake. We tested the hypothesis that iron overload can lead to cardiac mitochondrial dysfunction and that mitochondrial calcium uniporter (MCU) plays a major role for cardiac mitochondrial iron uptake under iron-overload condition. Cardiac mitochondrial function was assessed via the determination of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential changes.
Isolated cardiac mitochondria from male Wistar rats were used in this study. To determine the routes for cardiac mitochondrial iron uptake, isolated mitochondria were exposed to MCU blocker (Ru360), mitochondrial permeability transition pore (mPTP) blocker (cyclosporin A) and an iron chelator (deferoxamine).
We found that (i) iron overload caused cardiac mitochondrial dysfunction, indicated by increased ROS production, mitochondrial membrane depolarization and mitochondrial swelling; and (ii) only MCU blocker completely protected cardiac mitochondrial dysfunction caused by iron overload.
These findings strongly suggest that MCU could be the major route for iron uptake into cardiac mitochondria. The inhibition of MCU could be the novel pharmacological intervention for preventing iron-overload cardiomyopathy.
心脏中的铁过载可导致铁过载性心肌病和心律失常。在过去的几十年中，越来越多的证据表明，心脏线粒体功能障碍与心脏功能障碍和致命性心律失常的发展有关。尽管如此，铁过载对心脏线粒体功能的影响仍不清楚。在这项研究中，我们确定了铁过载对心脏线粒体功能的影响以及心脏线粒体铁摄取途径。我们假设铁过载可导致心脏线粒体功能障碍，并且在线粒体铁过载条件下，线粒体钙单向转运蛋白（MCU）在心脏线粒体铁摄取中起主要作用。通过测定线粒体肿胀、线粒体活性氧（ROS）产生和线粒体膜电位变化来评估心脏线粒体功能。
本研究使用雄性 Wistar 大鼠的心脏线粒体。为了确定心脏线粒体铁摄取途径，将分离的线粒体暴露于 MCU 阻断剂（Ru360）、线粒体通透性转换孔（mPTP）阻断剂（环孢菌素 A）和铁螯合剂（去铁胺）。
我们发现：（i）铁过载导致心脏线粒体功能障碍，表现为 ROS 产生增加、线粒体膜去极化和线粒体肿胀；（ii）只有 MCU 阻断剂可完全保护铁过载引起的心脏线粒体功能障碍。
这些发现强烈表明 MCU 可能是心脏线粒体摄取铁的主要途径。抑制 MCU 可能是预防铁过载性心肌病的新的药理学干预措施。
