Ren Youxiao, Wu Ling-Ling, Song Wenjing, Gao Yanan, Shao Litao, Lu Zhiyuan, Wang Songsong, Shao Xintian, Yu Zhenjie, Zhang Mengrui, Wu Jing, Han Liwen, Zeng Kewu, Chen Qixin
State Key Laboratory of Advanced Drug Delivery and Release Systems, School of Pharmaceutical Sciences, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, P. R. China.
Department of Traditional Chinese Medicine Orthopedics, Neck-Shoulder and Lumbocrural Pain Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250062, P. R. China.
Adv Sci (Weinh). 2025 Mar;12(9):e2410561. doi: 10.1002/advs.202410561. Epub 2025 Jan 13.
Mitochondrial quality control is paramount for cellular development, with mitochondrial electron flow (Mito-EF) playing a central role in maintaining mitochondrial homeostasis. However, unlike visible protein entities, which can be monitored through chemical biotechnology, regulating mitochondrial quality control by invisible entities such as Mito-EF has remained elusive. Here, a Mito-EF tracker (Mito-EFT) with a four-pronged probe design is presented to elucidate the dynamic mechanisms of Mito-EF's involvement in mitochondrial quality control. Heightened aggregation of Mito-EF in fiber-like healthy mitochondria compared to round-like damaged mitochondria is demonstrated, revealed Mito-EF aggregation correlated with mitochondrial morphological remodeling, particularly in regions undergoing mitochondrial fission and fusion, and show the Mito-EF signal associated with mitochondrial cristae maintained by Dynamin-Related Protein 1 (DRP1). This underscores the importance of considering Mito-EF in assessing mitochondrial quality control parameters. A novel drug screening evaluation parameter, Mito-EF is also introduced to screen and discover mitochondrial-targeted therapeutic modulators. This tracker provides new avenues for investigating the role of Mito-EF in maintaining mitochondrial homeostasis and quality control, offering a potent tool for assessing mitochondrial quality and drug screening.
线粒体质量控制对于细胞发育至关重要，线粒体电子流（Mito-EF）在维持线粒体稳态中发挥着核心作用。然而，与可通过化学生物技术监测的可见蛋白质实体不同，通过诸如Mito-EF等不可见实体来调节线粒体质量控制仍然难以捉摸。在此，提出了一种具有四叉探针设计的Mito-EF追踪器（Mito-EFT），以阐明Mito-EF参与线粒体质量控制的动态机制。结果表明，与圆形受损线粒体相比，纤维状健康线粒体中Mito-EF的聚集增强，揭示了Mito-EF聚集与线粒体形态重塑相关，特别是在经历线粒体分裂和融合的区域，并表明与线粒体嵴相关的Mito-EF信号由动力相关蛋白1（DRP1）维持。这突出了在评估线粒体质量控制参数时考虑Mito-EF的重要性。还引入了一个新的药物筛选评估参数Mito-EF，以筛选和发现线粒体靶向治疗调节剂。该追踪器为研究Mito-EF在维持线粒体稳态和质量控制中的作用提供了新途径，为评估线粒体质量和药物筛选提供了有力工具。
