Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
Cell Death Differ. 2024 Apr;31(4):387-404. doi: 10.1038/s41418-024-01284-8. Epub 2024 Mar 23.
The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.
细胞色素 c 是一种具有高度正电荷的氧化还原活性蛋白，调节着生与死的细胞命运决定。在正常生理条件下，细胞色素 c 定位于线粒体的膜间空间，在特定的病理或应激诱导条件下，其分布可扩展到细胞质、细胞核和细胞外空间。在线粒体中，细胞色素 c 作为电子传递链中的电子载体，促进三磷酸腺苷合成，调节心磷脂过氧化，影响活性氧物种动态。在细胞应激时，它可以被释放到细胞质中，在那里它与凋亡蛋白酶激活因子 1（APAF1）相互作用形成凋亡体，启动依赖半胱天冬酶的凋亡细胞死亡。此外，在暴露于促凋亡化合物后，细胞色素 c 有助于药物耐受持久细胞的存活。当转移到细胞核时，它可以诱导染色质凝聚并破坏核小体组装。当它被释放到细胞外空间时，细胞色素 c 可能在细胞死亡过程中充当免疫介质，突出其在细胞生物学中的多方面作用。在这篇综述中，我们探讨了细胞色素 c 在生理和病理反应中的多种结构和功能方面。我们总结了细胞色素 c 的翻译后修饰（如磷酸化、乙酰化、酪氨酸硝化和氧化）、结合蛋白（如 HIGD1A、CHCHD2、ITPR1 和核仁磷酸蛋白）和突变（如 G41S、Y48H 和 A51V）如何影响其功能。此外，我们还概述了用于检测细胞色素 c 的最新先进技术，以及与该蛋白相关的潜在治疗方法。这些策略在个性化医疗保健中具有巨大的潜力，为包括神经退行性疾病、心血管疾病和癌症在内的多种疾病提供了靶向干预的机会。
