A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species
A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species
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DOI：
10.1016/j.freeradbiomed.2011.02.033
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发表时间：
2011-06-01
影响因子：
7.4
通讯作者：
Morin, Didier
中科院分区：
文献类型：
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作者：
Lo Iacono, Luisa;Boczkowski, Jorge;Morin, Didier
一氧化碳（CO）是哺乳动物细胞中一种重要的信号介质，它是血红素加氧酶降解血红素过程中产生的。在这里，我们表明，精确交付CO分离的心脏线粒体使用水溶性CO释放分子（CORM-3）解偶联呼吸。添加低微摩尔浓度的CORM-3（1-20 μ M），但不是不释放CO的无活性化合物，以浓度依赖性方式显著增加线粒体耗氧速率（状态2呼吸）。相反，较高浓度的CORM-3（100 μ M）抑制ADP依赖的呼吸，通过抑制细胞色素c氧化酶。CORM-3介导的解偶联作用在CO清除剂肌红蛋白的存在下被抑制。此外，这种效果与膜电位（psi）随着时间的推移逐渐下降，并部分逆转丙二酸，复合物II活性的抑制剂。类似地，解偶联蛋白的抑制或腺嘌呤核苷酸转运蛋白的阻断减弱了CORM-3对状态2呼吸和Δ psi的影响。CORM-3增加了线粒体从复合物I-连接的底物（丙酮酸/苹果酸）呼吸产生的过氧化氢（H2 O2）。然而，呼吸启动通过复合物II使用琥珀酸导致过氧化氢的生产增加了五倍，这种效果被显着抑制CORM-3。这些发现揭示了CORM-3的反直觉作用，表明低水平的CO作为线粒体呼吸的重要调节剂。(C)2011 Elsevier Inc. All rights reserved.
Carbon monoxide (CO), produced during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator in mammalian cells. Here we show that precise delivery of CO to isolated heart mitochondria using a water-soluble CO-releasing molecule (CORM-3) uncouples respiration. Addition of low-micromolar concentrations of CORM-3 (1-20 mu M), but not an inactive compound that does not release CO, significantly increased mitochondrial oxygen consumption rate (State 2 respiration) in a concentration-dependent manner. In contrast, higher concentrations of CORM-3 (100 mu M) suppressed ADP-dependent respiration through inhibition of cytochrome c oxidase. The uncoupling effect mediated by CORM-3 was inhibited in the presence of the CO scavenger myoglobin. Moreover, this effect was associated with a gradual decrease in membrane potential (psi) over time and was partially reversed by malonate, an inhibitor of complex II activity. Similarly, inhibition of uncoupling proteins or blockade of adenine nucleotide transporter attenuated the effect of CORM-3 on both State 2 respiration and Delta psi. Hydrogen peroxide (H2O2) produced by mitochondria respiring from complex I-linked substrates (pyruvate/malate) was increased by CORM-3. However, respiration initiated via complex II using succinate resulted in a fivefold increase in H2O2 production and this effect was significantly inhibited by CORM-3. These findings disclose a counterintuitive action of CORM-3 suggesting that CO at low levels acts as an important regulator of mitochondrial respiration. (C) 2011 Elsevier Inc. All rights reserved.