Cytochrome c (Cytc)¹is 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.

细胞色素c（Cyt c）¹是一种细胞生死决定分子，它通过组织特异性的翻译后修饰来调节细胞能量的供应和凋亡。Cyt c是线粒体电子传输链（ETC）中的电子载体，因此是产生有氧能量的关键。在细胞应激条件下，Cyt c从线粒体释放是细胞凋亡的重要步骤，导致凋亡小体形成，胱天蛋白酶激活和细胞死亡。最近，Cyt c被证明是调节Cyt c功能的细胞信号通路的靶标。通过组织特异性磷酸化。到目前为止，已经绘制了Cyt c的五个磷酸化位点并进行了功能表征，分别是Tyr97，Tyr48，Thr28，Ser47和Thr58。所有五个磷酸化均部分抑制呼吸作用，我们建议在正常条件下可产生最佳的中间线粒体膜电位并降低ROS的产生。其中的四个磷酸化导致Cyt c的凋亡功能受到抑制，这提示磷酸化Cyt c的细胞保护作用。有趣的是，这些磷酸化在诸如缺血的应激条件下丢失。这导致在再灌注，线粒体膜电位超极化，过多的ROS产生和细胞凋亡期间产生最大的ETC通量。我们在这里提出一个新模型，该模型提出电子从Cyt c转移到细胞色素c氧化酶是ETC的限速步骤，它是通过Cyt c的翻译后修饰来调节的。这种调节在疾病状况下可能是功能失调的，例如缺血再灌注损伤和通过增加的ROS引起的神经退行性疾病或癌症，其中Cyt c上的翻译后修饰可能提供了逃避凋亡的机制。