Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC-treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

中文翻译：

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基于神经球蛋白的高亲和力配体阱可逆转一氧化碳诱导的线粒体中毒。

一氧化碳（CO）仍然是人类中毒的最常见原因。一氧化碳中毒的后果包括心脏功能障碍，脑损伤和死亡。CO通过与血红蛋白结合并抑制线粒体细胞色素C氧化酶（CcO）来引起毒性，从而减少氧的输送并抑制氧化磷酸化。我们最近开发了一种基于人类神经球蛋白（Ngb-H64Q-CCC）的CO解毒剂。在体外和体内，该分子增强了从红细胞中清除CO的能力。在此，我们测试了Ngb-H64Q-CCC是否也可以清除CcO中的CO，并减弱CO诱导的线粒体呼吸抑制。与未暴露的小鼠相比，暴露于3％CO的小鼠的心脏组织的组织呼吸速率降低了42±19％，CcO活性降低了33±38％。静脉输注Ngb-H64Q-CCC与对照组相比，与PBS处理，CO中毒小鼠相比，Ngb-H64Q-CCC处理的小鼠的呼吸速率与较高的电子传输链CcO活性相关。此外，使用Clark型氧电极，我们在存在和不存在CO（160μm）和一氧化氮（100μm）饱和溶液的情况下，测量了大鼠肝线粒体呼吸。一氧化碳和一氧化氮均抑制了呼吸作用，用Ngb-H64Q-CCC（分别为100和50μm）处理可显着逆转这种抑制作用。这些结果表明，Ngb-H64Q-CCC通过清除羧基血红蛋白中的CO，改善全身的氧气输送并逆转CO对线粒体的抑制作用来减轻CO毒性。