Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis
Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis
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DOI：
10.1016/j.biocel.2020.105704
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发表时间：
2020-04-01
影响因子：
4
通讯作者：
Huttemann, Maik
中科院分区：
文献类型：
--
作者：
Kalpage, Hasini A.;Wan, Junmei;Huttemann, Maik
细胞色素 c (Cytc)(1) 是一种细胞生死决定分子，通过组织特异性翻译后修饰调节细胞能量供应和细胞凋亡。 Cytc 是线粒体电子传递链 (ETC) 中的电子载体，因此是有氧能量产生的核心。在细胞应激条件下，线粒体释放的 Cytc 是细胞凋亡的关键步骤，导致凋亡体形成、半胱天冬酶激活和细胞死亡。最近，Cytc 被证明是细胞信号传导途径的靶标，通过组织特异性磷酸化调节 Cytc 的功能。到目前为止，Cytc 的 5 个磷酸化位点已被定位并进行功能表征：Tyr97、Tyr48、Thr28、Ser47 和 Thr58。所有五种磷酸化都部分抑制呼吸，我们认为这会在正常条件下产生最佳的中间线粒体膜电位和低活性氧产生。其中四个磷酸化导致 Cytc 凋亡功能的抑制，表明磷酸化 Cytc 具有细胞保护作用。有趣的是，这些磷酸化在缺血等应激条件下会丢失。这导致再灌注期间 ETC 通量最大、线粒体膜电位超极化、ROS 生成过多和细胞凋亡。我们在此提出一个新模型，提出从 Cytc 到细胞色素 c 氧化酶的电子转移是 ETC 的限速步骤，该步骤通过 Cytc 的翻译后修饰进行调节。这种调节可能在诸如缺血再灌注损伤和由于 ROS 增加而导致的神经退行性疾病或癌症等疾病中出现功能障碍，其中 Cytc 的翻译后修饰可能提供一种逃避细胞凋亡的机制。
Cytochrome c (Cytc)(1) is a cellular life and death decision molecule that regulates cellular energy supply and apoptosis through tissue specific post-translational modifications. Cytc is an electron carrier in the mitochondrial electron transport chain (ETC) and thus central for aerobic energy production. Under conditions of cellular stress, Cytc release from the mitochondria is a committing step for apoptosis, leading to apoptosome formation, caspase activation, and cell death. Recently, Cytc was shown to be a target of cellular signaling pathways that regulate the functions of Cytc by tissue-specific phosphorylations. So far five phosphorylation sites of Cytc have been mapped and functionally characterized, Tyr97, Tyr48, Thr28, Ser47, and Thr58. All five phosphorylations partially inhibit respiration, which we propose results in optimal intermediate mitochondrial membrane potentials and low ROS production under normal conditions. Four of the phosphorylations result in inhibition of the apoptotic functions of Cytc, suggesting a cytoprotective role for phosphorylated Cytc. Interestingly, these phosphorylations are lost during stress conditions such as ischemia. This results in maximal ETC flux during reperfusion, mitochondrial membrane potential hyperpolarization, excessive ROS generation, and apoptosis. We here present a new model proposing that the electron transfer from Cytc to cytochrome c oxidase is the rate-limiting step of the ETC, which is regulated via post-translational modifications of Cytc. This regulation may be dysfunctional in disease conditions such as ischemia-reperfusion injury and neurodegenerative disorders through increased ROS, or cancer, where post-translational modifications on Cytc may provide a mechanism to evade apoptosis.