title: Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload.
abstract: OBJECTIVE
  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 (mPTP) 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.
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Sripetchwandee
authors.forename: S B
authors.initials: SB
authors.lastname: KenKnight
authors.forename: J
authors.initials: J
authors.lastname: Sanit
authors.forename: S
authors.initials: S
authors.lastname: Chattipakorn
authors.forename: N
authors.initials: N
authors.lastname: Chattipakorn
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter
keywords: cardiac mitochondria; cardiac mitochondrial dysfunction; iron accumulation; mitochondrial membrane potential; mitochondrial swelling; reactive oxygen species