Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction

Changgong Wu, Lin Yan, Christophe Depre, Sunil K. Dhar, You Tang Shen, Junichi Sadoshima, Stephen F. Vatner, Dorothy E. Vatner

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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. H2O 2 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.

Original languageEnglish (US)
Pages (from-to)C928-C934
JournalAmerican Journal of Physiology - Cell Physiology
Volume297
Issue number4
DOIs
StatePublished - 2009

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Keywords

  • Cytochrome oxidase
  • Mitochondria
  • Myocardial ischemia
  • Oxidative stress

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