Department of Molecular & Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular & Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell. 2024 Aug 8;187(16):4289-4304.e26. doi: 10.1016/j.cell.2024.05.057. Epub 2024 Jun 27.
Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPR). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
细胞内环境稳态受到来自微环境的刺激的精细影响，包括信号分子、代谢物和病原体。线粒体作为细胞内的信号枢纽，整合来自不同细胞内区室的信息，以调节细胞信号和代谢。多项研究表明，线粒体可能对各种细胞外信号事件做出反应。然而，细胞外基质（ECM）的变化如何影响线粒体稳态来调节动物生理学还不太清楚。我们发现 ECM 重塑以一种进化上保守的方式改变线粒体稳态。在机制上，ECM 重塑触发 TGF-β 反应以诱导线粒体分裂和线粒体未折叠蛋白反应（UPR）。在机体水平上，ECM 重塑通过增强线粒体应激反应来促进动物对病原体的防御。我们推测，这种 ECM-线粒体串扰代表了一种古老的免疫途径，它可以检测感染或机械应激引起的 ECM 损伤，从而引发适应性的基于线粒体的免疫和代谢反应。
