title: Conformational change of mitochondrial complex I increases ROS sensitivity during ischemia.
abstract: OBJECTIVE
  Myocardial ischemia/reperfusion (I/R) is associated with mitochondrial dysfunction and subsequent cardiomyocyte death. The generation of excessive quantities of reactive oxygen species (ROS) and resultant damage to mitochondrial enzymes is considered an important mechanism underlying reperfusion injury. Mitochondrial complex I can exist in two interconvertible states: active (A) and deactive or dormant (D). We have studied the active/deactive (A/D) equilibrium in several tissues under ischemic conditions in vivo and investigated the sensitivity of both forms of the heart enzyme to ROS.
  
  
  RESULTS
  We found that in the heart, t½ of complex I deactivation during ischemia was 10 min, and that reperfusion resulted in the return of A/D equilibrium to its initial level. The rate of superoxide generation by complex I was higher in ischemic samples where content of the D-form was higher. Only the D-form was susceptible to inhibition by H2O2 or superoxide, whereas turnover-dependent activation of the enzyme resulted in formation of the A-form, which was much less sensitive to ROS. The mitochondrial-encoded subunit ND3, most likely responsible for the sensitivity of the D-form to ROS, was identified by redox difference gel electrophoresis.
  
  
  METHODS
  A combined in vivo and biochemical approach suggests that sensitivity of the mitochondrial system to ROS during myocardial I/R can be significantly affected by the conformational state of complex I, which may therefore represent a new therapeutic target in this setting.
  
  
  CONCLUSIONS
  The presented data suggest that transition of complex I into the D-form in the absence of oxygen may represent a key event in promoting cardiac injury during I/R.
authors: 1 Medical Biology Centre, School of Biological Sciences, Queen's University Belfast , Belfast, United Kingdom .
authors: Natalia
authors: N
authors: Gorenkova
authors: Emma
authors: E
authors: Robinson
authors: David J
authors: DJ
authors: Grieve
authors: Alexander
authors: A
authors: Galkin
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism*; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I