Energy crisis: the role of oxidative phosphorylation in acute inflammation and sepsis.
Energy crisis: the role of oxidative phosphorylation in acute inflammation and sepsis.
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DOI：
10.1016/j.bbadis.2014.05.031
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Hüttemann M
中科院分区：
文献类型：
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作者：
Lee I;Hüttemann M
线粒体功能障碍越来越被认为是大多数人类常见疾病的共犯，包括癌症、神经退行性变、糖尿病、心肌梗死和中风等缺血/再灌注损伤，以及脓毒症。炎症条件，无论是急性的还是慢性的，最近被证明影响线粒体的功能。我们在这里讨论氧化磷酸化(OxPhos)的作用，重点放在急性炎症条件下，特别是脓毒症和实验性脓毒症模型。我们讨论了线粒体的改变，特别是氧化代谢的抑制和线粒体活性氧在疾病病理中的作用。包括代谢、增殖和细胞因子信号在内的几个信号通路影响线粒体的功能，在炎症性疾病条件下似乎是重要的。细胞色素c氧化酶(COX)和细胞色素c是整个OxPhos系统的例子，因为它们在细胞信号转导方面已经得到了更详细的研究。细胞色素c除了线粒体呼吸外，还在细胞凋亡中发挥核心作用。我们提出了一个模型，在这个模型中，炎症信号导致线粒体蛋白的磷酸化状态发生变化，包括COX催化亚基I的Tyr304磷酸化，这导致OxPhos的抑制，线粒体膜电位的降低，从而导致能量不足，这可能导致器官衰竭和死亡，就像败血症患者一样。
Mitochondrial dysfunction is increasingly recognized as an accomplice in most of the common human diseases including cancer, neurodegeneration, diabetes, ischemia/reperfusion injury as seen in myocardial infarction and stroke, and sepsis. Inflammatory conditions, both acute and chronic, have recently been shown to affect mitochondrial function. We here discuss the role of oxidative phosphorylation (OxPhos), focusing on acute inflammatory conditions, in particular sepsis and experimental sepsis models. We discuss mitochondrial alterations, specifically suppression of oxidative metabolism and the role of mitochondrial reactive oxygen species in disease pathology. Several signaling pathways including metabolic, proliferative, and cytokine signaling affect mitochondrial function and appear to be important in inflammatory disease conditions. Cytochrome c oxidase (COX) and cytochrome c, the latter of which plays a central role in apoptosis in addition to mitochondrial respiration, serve as examples for the entire OxPhos system since they have been studied in more detail with respect to cell signaling. We propose a model in which inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, including Tyr304 phosphorylation of COX catalytic subunit I. This results in inhibition of OxPhos, a reduction of the mitochondrial membrane potential, and consequently a lack of energy, which can cause organ failure and death as seen in septic patients.