Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis
Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis
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DOI：
10.1097/01.shk.0000108400.56565.ab
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发表时间：
2004-02-01
期刊：
影响因子：
3.1
通讯作者：
Deutschman, CS
中科院分区：
文献类型：
--
作者：
Levy, RJ;Vijayasarathy, C;Deutschman, CS
脓毒症是全世界重症监护病房最常见的死亡原因。脓毒症的基本病理生理缺陷，导致许多器官系统的功能异常，仍然难以捉摸。一个潜在的原因是线粒体氧化磷酸化的破坏。在这里，我们报道心肌细胞色素c氧化酶（电子传递链的末端氧化酶）对细胞色素c的氧化在小鼠实验性败血症（盲肠结扎单次或双次23号穿刺）早期被竞争性抑制。在严重脓毒症（盲肠结扎和双穿刺，48 h死亡率75%）中，抑制在48 h后变为非竞争性。非竞争性抑制的发展与血红素a(3)含量的减少有关，血红素a(3)是功能亚基(1)的关键活性位点，并催化分子氧的减少。此外，盲肠结扎和双穿刺后，亚单位I mRNA和蛋白的稳态水平持续下降。血红素的缺失和亚基I的缺失都可以解释细胞色素c氧化酶的不可逆抑制。细胞色素c氧化酶的非竞争性抑制可能中断氧化磷酸化，导致败血症相关的心脏抑制。重要的是，这种异常可能是其他器官系统败血症相关功能障碍的基础。
Sepsis is the most common cause of death in intensive care units worldwide. The basic pathophysiologic defect in sepsis, causing functional abnormalities in many organ systems, remains elusive. One potential cause is disruption of oxidative phosphorylation in mitochondria. Here, we report that oxidation of cytochrome c by myocardial cytochrome c oxidase, the terminal oxidase in the electron transport chain, is competitively inhibited early in experimental sepsis (cecal ligation with single or double 23-gauge puncture) in mice. In severe sepsis (cecal ligation and double puncture, 75% mortality at 48 h), inhibition becomes noncompetitive by 48 h. The development of noncompetitive inhibition is associated with a decrease in heme a,a(3) content, which is the key active site in the functional subunit (1) and catalyzes the reduction of molecular oxygen. In addition, there are persistently decreased steady-state levels of subunit I mRNA and protein after cecal ligation and double puncture. Both loss of heme and loss of subunit I could explain the observed irreversible inhibition of cytochrome c oxidase. Noncompetitive inhibition of cytochrome c oxidase may interrupt oxidative phosphorylation, leading to sepsis-associated cardiac depression. Importantly, this abnormality may underlie sepsis-associated dysfunction in other organ systems.