2026年10月21日，南开大学于凡等科学家在《自然》发表研究，揭示了GRP75依赖的SIMPA介导细胞器间质量控制。

线粒体由双层膜包被，是半自主性细胞器，因而极易受到整体和内部蛋白质稳态应激的影响。为维持线粒体完整性和细胞健康，已演化出多种蛋白质稳态层面和细胞器间的监视机制。然而，蛋白质稳态损伤如何跨细胞器传递应激信号，以及质量监视机器如何协调这些功能，其精确机制仍不清楚。在此，研究人员报道，在蛋白质稳态应激下，受损的线粒体蛋白被隔离形成应激诱导的线粒体蛋白聚集体（SIMPA），这些聚集体以空间受限的方式激活特定的质量控制机制，而不扰动线粒体网络。定量蛋白质组学和关联光-电子显微镜分析显示，SIMPA通过线粒体-内质网接触位点或线粒体相关膜介导细胞器间通讯。机制上，GRP75协调SIMPA的生物发生，并通过线粒体-内质网接触位点或线粒体相关膜局部激活内质网未折叠蛋白反应通路，以靶向清除SIMPA。在功能上，研究人员在细胞和肝病模型中发现，GRP75依赖的SIMPA信号级联可减轻线粒体应激，并在蛋白毒性应激下保持线粒体完整性。总体而言，研究表明SIMPA作为蛋白凝聚体，充当线粒体质量控制的中心跨区室通讯枢纽，支持细胞和机体适应性。

附：英文原文

Title: GRP75-dependent SIMPA mediates inter-organellar quality control

Author: Yu, Fan, Jiang, Lingyu, Liu, Hanyu, Yang, Song, Yuan, Yuan, Jin, Hongzhen, Liu, Jinming, Liu, Xi, Dong, Yu, Ren, Dongfeng, Kang, Jie, Huang, Yan, Meng, Qi, Bai, Feng, Li, Yanjun, Li, Shuoguo, Liu, Huadong, Zhao, Wei, Xiao, Jia, Chen, Quan

Issue&Volume: 2026-10-21

Abstract: Mitochondria are bound by a double membrane and are semiautonomous organelles, rendering them highly vulnerable to global and internal proteostatic stress1. Multiple surveillance mechanisms at proteostatic and inter-organellar levels have evolved to maintain mitochondrial integrity and cellular health2,3,4,5,6,7. However, the precise mechanisms by which proteostatic damage relays stress signals across organelles and how the quality surveillance machinery coordinates these functions remain unknown. Here we report that under proteostatic stress, damaged mitochondrial proteins are sequestered to form stress-induced mitochondrial protein aggregates (SIMPAs) that activate specific quality control mechanisms in a spatially confined manner without perturbing the mitochondrial network. Quantitative proteomic and correlative light–electron microscopy analysis revealed that SIMPA mediates inter-organellar communication via mitochondria–endoplasmic reticulum contact sites or mitochondrial-associated membranes. Mechanistically, GRP75 coordinates SIMPA biogenesis and focally activates endoplasmic reticulum unfolded protein response pathways via mitochondria–endoplasmic reticulum contact sites or mitochondrial-associated membranes for the targeted clearance of SIMPAs. Functionally, in both cellular and liver disease models, we found that a GRP75-dependent SIMPA signalling cascade attenuates mitochondrial stress and preserves mitochondrial integrity under proteotoxic stress. Overall, we show that SIMPAs, functioning as protein condensates, serve as a central cross-compartment communication hub for mitochondrial quality control, supporting cellular and organismal fitness.

DOI: 10.1038/s41586-026-10733-y

Source:https://www.nature.com/articles/s41586-026-10733-y