Free radicals alter maximal diaphragmatic mitochondrial oxygen consumption in endotoxin-induced sepsis

Leigh A. Callahan, Daniel A. Stofan, Luke I. Szweda, David E. Nethery, Gerald S. Supinski

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Recent studies indicate that sepsis is associated with enhanced generation of several free radical species (nitric oxide, superoxide, hydrogen peroxide) in skeletal muscle. While studies suggest that free radical generation causes uncoupling of oxidative phosphorylation in sepsis, no previous report has examined the role of free radicals in modulating skeletal muscle oxygen consumption during State 3 respiration or inhibiting the electron transport chain in sepsis. The purpose of the present study was to examine the effects of endotoxin-induced sepsis on State 3 diaphragm mitochondrial oxygen utilization and to determine if inhibitors/scavengers of various free radical species would protect against these effects. We also examined mitochondrial protein electrophoretic patterns to determine if observed endotoxin-related physiological derangements were accompanied by overt alterations in protein composition. Studies were performed on: (a) control animals, (b) endotoxin-treated animals, (c) animals given endotoxin plus PEG-SOD, a superoxide scavenger, (d) animals given endotoxin plus L-NAME, a nitric oxide synthase inhibitor, (e) animals given only PEG-SOD or L-NAME, (f) animals given endotoxin plus D-NAME, and (g) animals given endotoxin plus denatured PEG-SOD. We found: (a) no alteration in maximal State 3 mitochondrial oxygen consumption rate at 24 h after endotoxin administration, but (b) a significant reduction in oxygen consumption rate at 48 h after endotoxin, (c) no effect of endotoxin to induce uncoupling of oxidative phosphorylation, (d) either PEG-SOD or L-NAME (but neither denatured PEG-SOD nor D-NAME) prevented endotoxin-mediated reductions in State 3 respiration rates, (e) some mitochondrial proteins underwent tyrosine nitrosylation at 24 h after endotoxin administration, and (f) SDS-page electrophoresis of mitochondria from endotoxin-treated animals revealed a selective depletion of several proteins at 48 h after endotoxin administration (but not at 24 h); (g) administration of L-NAME or PEG-SOD prevented this protein depletion. These data provide the first evidence that endotoxin-induced reductions in State 3 mitochondrial oxygen consumption are free radical-mediated.

Original languageEnglish (US)
Pages (from-to)129-138
Number of pages10
JournalFree Radical Biology and Medicine
Volume30
Issue number1
DOIs
StatePublished - Jan 1 2001

Fingerprint

Endotoxins
Oxygen Consumption
Free Radicals
Sepsis
Oxygen
Animals
NG-Nitroarginine Methyl Ester
Mitochondrial Proteins
Oxidative Phosphorylation
Superoxides
Muscle
Skeletal Muscle
Free Radical Scavengers
Proteins
Mitochondria
Respiratory Rate
Diaphragms
Electron Transport
Diaphragm
Electrophoresis

Keywords

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

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Medicine(all)
  • Toxicology

Cite this

Free radicals alter maximal diaphragmatic mitochondrial oxygen consumption in endotoxin-induced sepsis. / Callahan, Leigh A.; Stofan, Daniel A.; Szweda, Luke I.; Nethery, David E.; Supinski, Gerald S.

In: Free Radical Biology and Medicine, Vol. 30, No. 1, 01.01.2001, p. 129-138.

Research output: Contribution to journalArticle

Callahan, Leigh A. ; Stofan, Daniel A. ; Szweda, Luke I. ; Nethery, David E. ; Supinski, Gerald S. / Free radicals alter maximal diaphragmatic mitochondrial oxygen consumption in endotoxin-induced sepsis. In: Free Radical Biology and Medicine. 2001 ; Vol. 30, No. 1. pp. 129-138.
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