<br>实时观察完整线粒体内内源细胞色素 c 的构象变化和易位,Journal of the American Chemical Society

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实时观察完整线粒体内内源细胞色素 c 的构象变化和易位
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-02-09 , DOI: 10.1021/jacs.3c10216
Jianhua Zhan _{1,

2} , Danyun Zeng _{1,

2} , Xiong Xiao _{1,

2} , Zhongpei Fang _{1,

2} , Tao Huang _{1,

2} , Beibei Zhao _{1,

2} , Qinjun Zhu _{1,

2} , Caixiang Liu _{1,

2} , Bin Jiang _{1,

2,

3,

4} , Xin Zhou _{1,

2,

3,

4} , Conggang Li _{1,

2,

3} , Lichun He _{1,

2} , Daiwen Yang ₅ , Maili Liu _{1,

2,

3,

4} , Xu Zhang _{1,

2,

3,

4}

Affiliation

细胞色素 c (cyt c) 是一种具有不同构象的多功能蛋白质。然而，细胞色素c在其天然环境线粒体中的构象仍不清楚。在这里，我们应用核磁共振波谱来研究完整线粒体内内源细胞色素 c 在天然同位素丰度下的构象和位置，主要使用广泛的甲基作为探针。通过监测时间依赖性化学位移扰动，我们观察到大多数细胞色素 c 位于线粒体内膜并部分展开，这与其在溶液中的天然构象不同。当遭受氧化应激时，细胞色素c由于活性氧（ROS）增加而发生氧化修饰，减弱与膜的静电相互作用，并逐渐易位到线粒体内膜空间。同时，与正常细胞色素c相比，氧化修饰细胞色素c对细胞的杀伤力降低。我们的研究结果显着提高了对线粒体中细胞色素 c 调节 ROS 的分子机制的理解。此外，它还强调了核磁共振监测完整细胞或细胞器内天然同位素丰度的高浓度分子的潜力。

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Real-Time Observation of Conformational Changes and Translocation of Endogenous Cytochrome c within Intact Mitochondria

Cytochrome c (cyt c) is a multifunctional protein with varying conformations. However, the conformation of cyt c in its native environment, mitochondria, is still unclear. Here, we applied NMR spectroscopy to investigate the conformation and location of endogenous cyt c within intact mitochondria at natural isotopic abundance, mainly using widespread methyl groups as probes. By monitoring time-dependent chemical shift perturbations, we observed that most cyt c is located in the inner mitochondrial membrane and partially unfolded, which is distinct from its native conformation in solution. When suffering oxidative stress, cyt c underwent oxidative modifications due to increasing reactive oxygen species (ROS), weakening electrostatic interactions with the membrane, and gradually translocating into the inner membrane spaces of mitochondria. Meanwhile, the lethality of oxidatively modified cyt c to cells was reduced compared with normal cyt c. Our findings significantly improve the understanding of the molecular mechanisms underlying the regulation of ROS by cyt c in mitochondria. Moreover, it highlights the potential of NMR to monitor high-concentration molecules at a natural isotopic abundance within intact cells or organelles.

更新日期：2024-02-09

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