Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation.
Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation.
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DOI：
10.1016/j.bbabio.2011.07.001
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发表时间：
2012-04
影响因子：
4.3
通讯作者：
Lee, Icksoo
中科院分区：
文献类型：
--
作者：
Huettemann, Maik;Helling, Stefan;Sanderson, Thomas H.;Sinkler, Christopher;Samavati, Lobelia;Mahapatra, Gargi;Varughese, Ashwathy;Lu, Guorong;Liu, Jenney;Ramzan, Rabia;Vogt, Sebastian;Grossman, Lawrence I.;Doan, Jeffrey W.;Marcus, Katrin;Lee, Icksoo
细胞色素c（Cytc）和细胞色素c氧化酶（考克斯）催化线粒体电子传递链（ETC）的末端反应，即氧还原为水。这一不可逆步骤受到高度调节，如存在组织特异性和发育表达的同种型、变构调节和可逆磷酸化所示，这些在Cytc和考克斯中都有发现。ETC在健康和疾病中的关键作用是显而易见的，因为它与ATP合酶一起提供了绝大多数细胞能量，驱动所有细胞过程。然而，在应激条件下，ETC产生活性氧（ROS），其导致细胞损伤并触发死亡过程。在这里，我们讨论目前的知识，细胞色素C和考克斯的调节，重点是细胞信号通路，包括cAMP/蛋白激酶A和酪氨酸激酶信号。基于晶体结构，我们突出了所有确定的磷酸化位点的Cytc和考克斯，我们提出了一个新的磷酸化位点，Ser 126上的考克斯亚基II。最后，我们得出一个模型，连接细胞信号与磷酸化状态的细胞色素C和考克斯。这反过来又调节它们的酶活性、线粒体膜电位以及ATP和ROS的产生。我们的模型是通过两个不同的人类病理学，急性炎症中看到的败血症，磷酸化导致强烈的考克斯抑制，然后能量消耗，和缺血/再灌注损伤，其中过度活跃的ETC复合物产生病理性高线粒体膜电位，导致过量的ROS生产。虽然在ETC活性谱的相反两极操作，但这两种情况都可以通过能量剥夺或ROS触发的细胞凋亡导致细胞死亡。
Cytochrome c (Cytc) and cytochrome c oxidase (COX) catalyze the terminal reaction of the mitochondrial electron transport chain (ETC), the reduction of oxygen to water. This irreversible step is highly regulated, as indicated by the presence of tissue-specific and developmentally expressed isoforms, allosteric regulation, and reversible phosphorylations, which are found in both Cytc and COX. The crucial role of the ETC in health and disease is obvious since it, together with ATP synthase, provides the vast majority of cellular energy, which drives all cellular processes. However, under conditions of stress, the ETC generates reactive oxygen species (ROS), which cause cell damage and trigger death processes. We here discuss current knowledge of the regulation of Cytc and COX with a focus on cell signaling pathways, including cAMP/protein kinase A and tyrosine kinase signaling. Based on the crystal structures we highlight all identified phosphorylation sites on Cytc and COX, and we present a new phosphorylation site, Ser126 on COX subunit II. We conclude with a model that links cell signaling with the phosphorylation state of Cytc and COX. This in turn regulates their enzymatic activities, the mitochondrial membrane potential, and the production of ATP and ROS. Our model is discussed through two distinct human pathologies, acute inflammation as seen in sepsis, where phosphorylation leads to strong COX inhibition followed by energy depletion, and ischemia/reperfusion injury, where hyperactive ETC complexes generate pathologically high mitochondrial membrane potentials, leading to excessive ROS production. Although operating at opposite poles of the ETC activity spectrum, both conditions can lead to cell death through energy deprivation or ROS-triggered apoptosis.
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影响因子：
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Parsons, Sarah J.
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Parsons, SJ
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