Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction.
Cytochrome c oxidase (COX) is composed of 13 subunits, of which COX I, II, and III are encoded by a mitochondrial gene. COX I and II function as the main catalytic components, but the function of COX III is unclear. Because myocardial ischemia affects mitochondrial oxidative metabolism, we hypothesized that COX activity and expression would be affected during postischemic cardiomyopathy. This hypothesis was tested in a monkey model following myocardial infarction (MI) and subsequent pacing-induced heart failure (HF). In this model, COX I protein expression was decreased threefold after MI and fourfold after HF (P < 0.05 vs. sham), whereas COX II expression remained unchanged. COX III protein expression increased 5-fold after MI and further increased 10-fold after HF compared with sham (P < 0.05 vs. sham). The physiological impact of COX III regulation was examined in vitro. Overexpression of COX III in mitochondria of HL-1 cells resulted in an 80% decrease in COX I, 60% decrease in global COX activity, 60% decrease in cell viability, and threefold increase in apoptosis (P < 0.05). Oxidative stress induced by H2O2 significantly (P < 0.05) increased COX III expression. H2O2 decreased cell viability by 47 +/- 3% upon overexpression of COX III, but only by 12 +/- 5% in control conditions (P < 0.05). We conclude that ischemic stress in vivo and oxidative stress in vitro lead to upregulation of COX III, followed by downregulation of COX I expression, impaired COX oxidative activity, and increased apoptosis. Therefore, upregulation of COX III may contribute to the increased susceptibility to apoptosis following MI and subsequent HF.
Wu
Changgong
C
Department of Cell Biology and Molecular Medicine and Cardiovascular Research Institute, Univeristy of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA.
Yan
Lin
L
Depre
Christophe
C
Dhar
Sunil K
SK
Shen
You-Tang
YT
Sadoshima
Junichi
J
Vatner
Stephen F
SF
Vatner
Dorothy E
DE
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003576:Electron Transport Complex IV / Q000502:physiology*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D032342:Muscle Cells / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D021122:Protein Subunits; D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV