State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, PR China.
State Key Laboratory of Physical Chemistry Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, PR China.
Int J Biol Macromol. 2024 Nov;279(Pt 1):135160. doi: 10.1016/j.ijbiomac.2024.135160. Epub 2024 Aug 29.
The crosstalk between endoplasmic reticulum and mitochondria is of significance in apoptosis, in which cytochrome b (Cyt b) is thought to be a major target for cytochrome c (Cyt c) upon its release from the mitochondria. In the absence of Cyt b, the role of interactions of Cyt c with CYP-dependent monooxygenase system in apoptotic regulation was explored in this study. NADPH-dependent and Cyt c-induced formation of reactive oxygen species (ROS) and NADPH-independent Cyt c unfolding were revealed. With the aid of a CPR inhibitor and CYP antibodies, the interactions among Cyt c, cytochrome P450 reductase (CPR) and cytochrome P450 (CYP) are evidenced, which are found crucial for monooxygenase-derived ROS formation. The underlying structural basis of Cyt c-CYP complex was unveiled by molecular dynamics simulations. This study provides novel insights into how Cyt c regulates ROS formation through the interactions with CPR and CYP, and is implicated for a deeper understanding of the regulation mechanism in the mitochondria-endoplasmic reticulum apoptotic pathway.
内质网和线粒体之间的串扰在细胞凋亡中具有重要意义，其中细胞色素 b（Cyt b）被认为是细胞色素 c（Cyt c）从线粒体释放后的主要靶标。在缺乏 Cyt b 的情况下，本研究探索了 Cyt c 与 CYP 依赖性单加氧酶系统相互作用在凋亡调控中的作用。揭示了 NADPH 依赖性和 Cyt c 诱导的活性氧（ROS）形成以及 NADPH 非依赖性 Cyt c 展开。借助 CPR 抑制剂和 CYP 抗体，证明了 Cyt c、细胞色素 P450 还原酶（CPR）和细胞色素 P450（CYP）之间的相互作用对于单加氧酶衍生的 ROS 形成至关重要。通过分子动力学模拟揭示了 Cyt c-CYP 复合物的潜在结构基础。这项研究提供了关于 Cyt c 如何通过与 CPR 和 CYP 的相互作用调节 ROS 形成的新见解，并为深入了解线粒体-内质网凋亡途径的调节机制提供了依据。
