Abstract：
Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.
摘要：
线粒体和内质网（ER）具有协同关系，是维持细胞稳态的关键调控中心。这些细胞器之间的交流是由线粒体ER接触位点（MERCS）介导的，允许材料和信息的交换，调节钙稳态，氧化还原信号，脂质转移和线粒体动力学的调节。MERCS是动态结构，允许细胞在正常稳态条件下响应细胞内环境的变化，而它们的组装/拆卸受到衰老和疾病等病理生理条件的影响。内质网腔中蛋白质折叠的破坏可以激活未折叠蛋白质反应（UPR），促进ER膜的重塑和MERCS的形成。UPR应激受体激酶PERK和IRE1位于或接近MERCS。UPR信令可以是自适应的或适应不良的，取决于蛋白质折叠或内质网应激的破坏是短暂的还是持续的。通过MERCS的适应性UPR信号可以增加线粒体钙的输入，新陈代谢和动力学，而适应性不良的UPR信号传导可导致过量的钙输入和凋亡途径的激活。靶向UPR信号传导和MERCS的组装是用于一系列与年龄相关的病症如神经变性和少肌症的有吸引力的治疗方法。这篇综述强调了与氧化还原介导的UPR激活在协调ER和线粒体之间的细胞器间通信中的作用有关的新兴证据。最终决定细胞功能和命运。
