title: Calcium-induced cardiac mitochondrial dysfunction is predominantly mediated by cyclosporine A-dependent mitochondrial permeability transition pore.
abstract: OBJECTIVE
  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: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Thailand.
authors: Chontida
authors: C
authors: Yarana
authors: Jirapas
authors: J
authors: Sripetchwandee
authors: Jantira
authors: J
authors: Sanit
authors: Siriporn
authors: S
authors: Chattipakorn
authors: Nipon
authors: N
authors: Chattipakorn
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D017975:Ruthenium Compounds / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; C112020:Ru 360; D017975:Ruthenium Compounds; C034703:mitochondrial calcium uniporter; D016572:Cyclosporine; D002118:Calcium