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.
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.
Authors: Xuechao Han; Jingman Xu; Sen Xu; Yahan Sun; Mali He; Xiaodong Li; Xinyu Li; Jiayi Pi; Rui Yu; Wei Tian Journal: Nan Fang Yi Ke Da Xue Xue Bao Date: 2018-11-30
Authors: Shanna Hamilton; Radmila Terentyeva; Tae Yun Kim; Peter Bronk; Richard T Clements; Jin O-Uchi; György Csordás; Bum-Rak Choi; Dmitry Terentyev Journal: Front Physiol Date: 2018-12-21 Impact factor: 4.566