Calcium-induced Cardiac Mitochondrial Dysfunction Is Predominantly Mediated by Cyclosporine A-dependent Mitochondrial Permeability Transition Pore

Background and Aims. Cardiac mitochondrial Ca2+ overload plays a critical role in mechanical and electrical dysfunction leading to cardiac cell death and fatal arrhythmia. Because Ca2+ overload is related to mitochondrial permeability transition, reactive oxygen species (ROS) production and membrane potential (Delta Psi m) dissipation, we probed the mechanistic association between Ca2+ overload, oxidative stress, mitochondrial permeability transition pore (mPTP) and mitochondrial calcium uniporter (MCU) in isolated cardiac mitochondria. Methods. Various concentrations of Ca2+ (5-200 mu M) 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 Ca2+-induced mitochondrial dysfunction. Results. High concentrations of Ca2+ (>= 100 mu M) caused overt mitochondrial swelling and Delta Psi m 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 Ca2+-induced cardiac mitochondrial dysfunction was mediated through the mPTP rather than MCU. Therefore, CsA could be more effective than Ru360 in preventing Ca2+-induced cardiac mitochondrial dysfunction. (C) 2012 IMSS. Published by Elsevier Inc.