Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.

中文翻译：

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通过严格控制细胞色素 c 氧化酶调节健康和疾病中的线粒体氧化磷酸化 – 对缺血/再灌注损伤、炎症性疾病、糖尿病和癌症的影响


线粒体对细胞功能至关重要，因为它们产生大部分细胞 ATP，通过氧化磷酸化介导，氧化磷酸化将电子传递链 （ETC） 的质子泵与 ATP 产生耦合。ETC 产生一个电化学梯度，称为质子驱动力，由线粒体膜电位（ΔΨm，哺乳动物的主要成分）和穿过线粒体内膜的 ΔpH 组成。ATP 的产生和活性氧 （ROS） 都与 ΔΨm 有关，并且已经表明 ΔΨm 的不平衡超出生理最佳中间范围会导致 ROS 的过量产生。ETC 的细胞色素 c 氧化酶 （COX） 与其小电子供体细胞色素 c （Cytc） 的反应是生理条件下哺乳动物中提出的限速步骤。这种氧化还原反应发生的速率控制 ΔΨm，从而控制 ATP 和 ROS 的产生。有多种机制可以调节这种反应，以满足细胞的能量需求并应对急性压力。COX 和 Cytc 已被证明受所有三种主要机制的调节，我们详细讨论了这些机制：变构调节、组织特异性亚型和翻译后修饰，为此我们提供了它们功能作用的全面目录和讨论，分别在 COX 上鉴定了 55 个和 50 个磷酸化和乙酰化位点。在几种常见的人类疾病中发现了这些调节机制的破坏，包括中风和心肌梗塞、包括败血症在内的炎症和糖尿病，其中 COX 或 Cytc 磷酸化的变化导致线粒体功能障碍，从而导致疾病病理生理学。 识别和随后靶向潜在的信号通路为未来改善人类健康的干预措施带来了明显的希望。一个例子干预措施是最近发现的无创 COX 抑制红外光疗法，它有望改变当前 COX 调节出错的疾病条件下的临床护理标准。