Li Jeson J, Xin Nan, Yang Chunxia, Kim Bo G, Tavizon Larissa A, Hong Ruth, Park Jina, Moore Travis I, Tharyan Rebecca George, Antebi Adam, Kim Hyun-Eui
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, United States of America.
PLoS Genet. 2025 May 8;21(5):e1011700. doi: 10.1371/journal.pgen.1011700. eCollection 2025 May.
Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2α signaling pathway, increasing phosphorylation of eIF2α and improving the ER's ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.
维持蛋白质稳态对细胞健康至关重要。我们之前的研究发现了一种跨区室的线粒体到胞质应激反应，它由线粒体蛋白质稳态的扰动激活，最终导致胞质中蛋白质稳态的改善。在这里，我们发现这个信号轴也影响内质网的未折叠蛋白反应（UPRER），提示存在线粒体到内质网应激反应（MERSR）。在MERSR过程中，UPRER的IRE1分支被抑制，引入了一个先前未知的MCSR调节成分。此外，通过上调PERK-eIF2α信号通路增强蛋白质稳态，增加eIF2α的磷酸化并提高内质网处理蛋白质稳态的能力。在表达多聚谷氨酰胺和淀粉样β肽的秀丽隐杆线虫疾病模型中，MERSR激活也导致聚集体负担和总体疾病结果的改善。这些发现揭示了线粒体和内质网在维持细胞蛋白质稳态方面的协调作用，并为区室间信号传导的重要性提供了进一步证据。
