Inhibition of cellular respiration by endogenously produced carbon monoxide

Grabriela D'Amico, Francis Lam, Thilo Hagen, Salvador Moncada

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Endogenously produced nitric oxide (NO) interacts with mitochondrial cytochrome c oxidase, leading to inhibition of cellular respiration. This interaction has been shown to have important physiological and pathophysiological consequences. Exogenous carbon monoxide (CO) is also known to inhibit cytochrome c oxidase in vitro; however, it is not clear whether endogenously produced CO can inhibit cellular respiration and, if so, what the significance of this might be. In this study, we show that exogenous CO inhibits respiration in a moderate but persistent manner in HEK293 cells under ambient (21%) oxygen concentrations (Ki=1.44 μM). This effect of CO was increased (Ki=0.35 μM) by incubation in hypoxic conditions (1% oxygen). Endogenous CO, generated by HEK293 cells transfected with the inducible isoform of haem oxygenase (haem oxygenase-1; HO-1), also inhibited cellular respiration moderately (by 12%) and this was accompanied by inhibition (23%) of cytochrome c oxidase activity. When the cells were incubated in hypoxic conditions during HO-1 induction, the inhibitory effect of CO on cell respiration was markedly increased to 70%. Furthermore, endogenously produced CO was found to be responsible for the respiratory inhibition that occurs in RAW264.7 cells activated in hypoxic conditions with lipopolysaccharide and interferon-γ, in the presence of N-(iminoethyl)-L-ornithine to prevent the synthesis of NO. Our results indicate that CO contributes significantly to the respiratory inhibition in activated cells, particularly under hypoxic conditions. Inhibition of cell respiration by endogenous CO through its interaction with cytochrome c oxidase might have an important role in inflammatory and hypoxic conditions.
    Original languageEnglish
    Pages (from-to)2291-2298
    Number of pages7
    JournalJournal of Cell Science
    Volume119
    Issue number11
    DOIs
    Publication statusPublished - 1 Jun 2006

    Keywords

    • Carbon monoxide
    • Hypoxia
    • Mitochondria
    • Nitric oxide
    • Respiration

    Fingerprint

    Dive into the research topics of 'Inhibition of cellular respiration by endogenously produced carbon monoxide'. Together they form a unique fingerprint.

    Cite this