Inhibition of cellular respiration by endogenously produced carbon monoxide
Inhibition of cellular respiration by endogenously produced carbon monoxide
复制标题
DOI：
10.1242/jcs.02914
复制
发表时间：
2006-06-01
影响因子：
4
通讯作者：
Moncada, Salvador
中科院分区：
文献类型：
--
作者：
D'Amico, Gabriela;Lam, Francis;Moncada, Salvador
内源性产生的一氧化氮（NO）与线粒体细胞色素c氧化酶相互作用，导致细胞呼吸抑制。这种相互作用已被证明具有重要的生理和病理生理后果。外源性一氧化碳（CO）也被称为抑制细胞色素c氧化酶在体外，但是，目前还不清楚是否内源性产生的CO可以抑制细胞呼吸，如果是这样，这可能是什么意义。在这项研究中，我们表明，外源性CO抑制呼吸在一个温和的，但持久的方式在HEK 293细胞环境（21%）氧浓度（Ki = 1.44 μ M）。这种效果的CO增加（Ki = 0.35 μ M），通过在缺氧条件下（1%氧）孵育。内源性CO，产生的HEK 293细胞转染诱导型血红素加氧酶（血红素加氧酶-1，HO-1），也抑制细胞呼吸中度（12%），这是伴随着抑制（23%）的细胞色素c氧化酶活性。当细胞在缺氧条件下孵育时，CO对HO-1诱导的细胞呼吸的抑制作用显著增加至70%。此外，内源性产生的CO被认为是负责呼吸抑制，发生在RAW264.7细胞在缺氧条件下激活的脂多糖和干扰素-γ，在存在的N-（亚氨基乙基）-L-鸟氨酸，以防止NO的合成。我们的研究结果表明，CO有助于显着的呼吸抑制在激活的细胞，特别是在缺氧条件下。内源性CO通过与细胞色素c氧化酶的相互作用抑制细胞呼吸可能在炎症和缺氧条件下起重要作用。
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 (K-i= 1.44 mu M). This effect of CO was increased (K-i = 0.35 mu M) 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-gamma, 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.