title: Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis.
abstract: Sepsis is the most common cause of death in intensive care units worldwide. The basic pathophysiologic defect in sepsis, causing functional abnormalities in many organ systems, remains elusive. One potential cause is disruption of oxidative phosphorylation in mitochondria. Here, we report that oxidation of cytochrome c by myocardial cytochrome c oxidase, the terminal oxidase in the electron transport chain, is competitively inhibited early in experimental sepsis (cecal ligation with single or double 23-gauge puncture) in mice. In severe sepsis (cecal ligation and double puncture, 75% mortality at 48 h), inhibition becomes noncompetitive by 48 h. The development of noncompetitive inhibition is associated with a decrease in heme a,a3 content, which is the key active site in the functional subunit (I) and catalyzes the reduction of molecular oxygen. In addition, there are persistently decreased steady-state levels of subunit I mRNA and protein after cecal ligation and double puncture. Both loss of heme and loss of subunit I could explain the observed irreversible inhibition of cytochrome c oxidase. Noncompetitive inhibition of cytochrome c oxidase may interrupt oxidative phosphorylation, leading to sepsis-associated cardiac depression. Importantly, this abnormality may underlie sepsis-associated dysfunction in other organ systems.
authors.affiliation: Department of Anesthesia, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
authors.forename: C
authors.initials: C
authors.lastname: Vijayasarathy
authors.forename: Nichelle R
authors.initials: NR
authors.lastname: Raj
authors.forename: Narayan G
authors.initials: NG
authors.lastname: Avadhani
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D015152:Blotting, Northern; D015153:Blotting, Western; D002432:Cecum / Q000293:injuries / Q000473:pathology; D004195:Disease Models, Animal; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000737:chemistry* / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D015151:Immunoblotting; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000473:pathology*; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D006418:Heme; D003576:Electron Transport Complex IV; D010100:Oxygen