Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

中文翻译：

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内源性一氧化碳信号调节线粒体功能和细胞内葡萄糖利用：血红素加氧酶底物血红素的影响。

应激诱导的血红素加氧酶-1（HO-1）催化血红素的氧化裂解，生成胆绿素，亚铁和一氧化碳（CO）。血红素加氧酶活性归因于通过胆绿素和胆红素的氧化还原循环系统的抗氧化防御。越来越多的证据表明，CO是一种气体信号分子，并在能量代谢的调节中起作用。CO对呼吸链的抑制作用已被很好地建立，但是这种过程对细胞应激反应的影响尚不十分清楚。通过细胞外通量分析和同位素示踪，我们研究了从CO供体CORM-401释放或血红素加氧酶内生产生的CO对呼吸链和葡萄糖代谢的影响。因此，CORM-401用作模拟血红素加氧酶产生内源性CO的工具。在长期（> 60分钟）中，CORM-401衍生的CO暴露抑制了线粒体呼吸，其被糖酵解增加，ATP产生速率降低和质子泄漏增加所抵消。在血红素加氧酶产生内源性CO后，同样观察到这种作用模式。但是，在目前情况下，只有在提供足够的血红素加氧酶（血红素）底物时才能观察到这些作用。HO-1蛋白水平的调节不太重要。CO通过糖酵解对葡萄糖代谢的长期影响之前，是细胞对CO的短期反应（<30分钟）。稳定的同位素标记实验和代谢通量分析表明，葡萄糖消耗的短期变化是从糖酵解转变为磷酸戊糖途径（PPP），同时活性氧（ROS）的产生也有所增加。总体而言，我们建议内源性CO的信号传导通过PPP刺激还原当量（NADPH）的快速形成，并在抗氧化防御中发挥其他作用，例如，通过胆红素/胆红素氧化还原循环系统的前馈刺激。