Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis
Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis
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DOI：
10.1164/rccm.201003-0326oc
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发表时间：
2010-09-15
影响因子：
24.7
通讯作者：
Singer, Mervyn
中科院分区：
文献类型：
--
作者：
Carre, Jane E.;Orban, Jean-Christophe;Singer, Mervyn
基本原理：我们先前报道了多器官衰竭脓毒症患者肌肉能量状态和线粒体功能障碍的结果相关性下降。我们假设幸存者有更大的能力来维持或恢复正常的线粒体functional.Objectives：为了确定是否线粒体生物合成，促进线粒体能力的过程，在危重患者中受到影响。方法：肌肉活组织检查取自16名最近入住重症监护室的重症患者（平均1-2天）和10名健康、年龄匹配的择期髋关节手术患者。存活率、线粒体形态、线粒体蛋白含量和酶活性、线粒体生物发生因子mRNA、微阵列分析，并测定磷酸化（能量）代谢物。16名重症患者中有10人在重症监护中幸存下来。线粒体大小随结局恶化而增加，提示肿胀。呼吸道蛋白亚基和转录本在重症患者中耗尽，在更大程度上在非幸存者中耗尽。过氧化物酶体增殖物激活受体γ共激活因子1-α（线粒体生物合成的转录共激活因子）的mRNA含量仅在幸存者中升高，线粒体氧化应激蛋白锰超氧化物歧化酶也是如此。最终的幸存者表现出升高的肌肉ATP和降低磷酸肌酸/ATP ratio.Conclusions：最终的幸存者应对早期与线粒体生物合成和抗氧化防御反应的危重病。这些反应可以部分抵消线粒体蛋白质的消耗，帮助维持功能和能量状态。在非幸存者中，受损的反应可能会增加对线粒体损伤和细胞能量衰竭的易感性，或阻碍恢复正常功能的能力。
Rationale: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality.Objectives: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients.Methods: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery.Measurements and Main Results: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio.Conclusions: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function.