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Background and Aims: Cardiac mitochondrial Ca(2+) overload plays a critical role in mechanical and electrical dysfunction leading to cardiac cell death and fatal arrhythmia. Because Ca(2+) overload is related to mitochondrial permeability transition, reactive oxygen species (ROS) production and membrane potential (ΔΨm) dissipation, we probed the mechanistic association between Ca(2+) overload, oxidative stress, mitochondrial permeability transition pore (mPTP) and mitochondrial calcium uniporter (MCU) in isolated cardiac mitochondria., Methods: Various concentrations of Ca(2+) (5-200 μM) were used to induce mitochondrial dysfunction. Cyclosporin A (CsA, an mPTP blocker) and Ru360 (an MCU blocker) were used to test its protective effects on Ca(2+)-induced mitochondrial dysfunction., Results: High concentrations of Ca(2+) (≥100 μM) caused overt mitochondrial swelling and ΔΨm collapse. However, only slight increases in ROS production were detected. Blocking the MCU by Ru360 is less effective in protecting mitochondrial dysfunction., Conclusions: A dominant cause of Ca(2+)-induced cardiac mitochondrial dysfunction was mediated through the mPTP rather than MCU. Therefore, CsA could be more effective than Ru360 in preventing Ca(2+)-induced cardiac mitochondrial dysfunction., (Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.)

Aim 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. Methods 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 (m PTP) blocker (cyclosporin A) and an iron chelator (deferoxamine). Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]