PLA2 dependence of diaphragm mitochondrial formation of reactive oxygen species

D. Nethery, L. A. Callahan, D. Stofan, R. Mattera, A. DiMarco, G. Supinski

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Contraction-induced respiratory muscle fatigue and sepsis- related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A2 (PLA2)-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA2 activity. To test these hypotheses, we examined H2O2 generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA2 inhibitors on H2O2 formation. We found that 1) calcium and ADP stimulated H2O2 formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H2O2 formation than mitochondria from control animals under basal, calcium-stimulated, and ADP- stimulated conditions; and 3) inhibitors of 14-kDa PLA2 blocked the enhanced H2O2 generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA2 activation) increased mitochondrial H2O2 formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA2 activation.

Original languageEnglish
Pages (from-to)72-80
Number of pages9
JournalJournal of Applied Physiology
Volume89
Issue number1
DOIs
StatePublished - Jul 2000

Keywords

  • Diaphragm
  • Free radicals
  • Mitochondria
  • Phospholipase
  • Respiratory muscles
  • Skeletal muscle

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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