This review discusses the role of redox regulation in the unfolded protein response (UPR) and mitochondrial-ER contact sites (MERCS) in maintaining cellular homeostasis. Mitochondria and the endoplasmic reticulum (ER) are key regulatory hubs that communicate through MERCS, which facilitate the exchange of material and information, modulate calcium homeostasis, redox signaling, lipid transfer, and mitochondrial dynamics. MERCS are dynamic structures that respond to changes in the intracellular environment, and their assembly and disassembly are affected by pathophysiological conditions such as aging and disease. Disruption of protein folding in the ER lumen can activate the UPR, promoting ER membrane remodeling and MERCS formation. The UPR is mediated by three branches: IRE1α, PERK, and ATF6. These receptors are located at or near MERCS and can be either adaptive or maladaptive, depending on whether the stress is transient or sustained. Adaptive UPR signaling via MERCS can increase mitochondrial calcium import, metabolism, and dynamics, while maladaptive UPR signaling can lead to excessive calcium import and activation of apoptotic pathways. Targeting UPR signaling and MERCS assembly is an attractive therapeutic approach for age-related conditions such as neurodegeneration and sarcopenia. The review highlights the emerging evidence related to the role of redox-mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, ultimately determining cell function and fate. The redox environment of the ER is closely linked to the initiation of ER stress and UPR activation. The ER has a more oxidizing environment compared to the cytosol, which facilitates thiol-disulfide exchange for correct protein folding. The redox state of the ER can also influence the activation of the UPR. The ER is the main Ca²+ store in metazoan cells, regulating Ca²+ homeostasis, which is vital for cellular function. The ER and mitochondria are linked at MERCS, facilitating the dynamic flow of information between the organelles, allowing changes in ER homeostasis to regulate mitochondrial function. Mitochondrial dynamics are regulated by the balance between biogenesis, fusion, fission, and mitophagy. The redox environment also regulates mitochondrial dynamics, with distinct ROS signatures at sites of mitochondrial fission. Disrupted mitophagy can result in the accumulation of dysfunctional mitochondria and is associated with age-related diseases. Mitochondrial stress can activate the UPRmt, particularly ATF5, to resolve proteotoxic and oxidative stress. The redox environment of mitochondria is crucial for their function, as mitochondrial respiration generates ATP but can also result in ROS generation. Mitochondrial ROS generation has been identified as a major cause of oxidative damage in conditions such as ischemia. The redox environment of the ER and mitochondria is essential for maintaining cellular homeostasis and regulating inter-organelle communication. The regulation ofThis review discusses the role of redox regulation in the unfolded protein response (UPR) and mitochondrial-ER contact sites (MERCS) in maintaining cellular homeostasis. Mitochondria and the endoplasmic reticulum (ER) are key regulatory hubs that communicate through MERCS, which facilitate the exchange of material and information, modulate calcium homeostasis, redox signaling, lipid transfer, and mitochondrial dynamics. MERCS are dynamic structures that respond to changes in the intracellular environment, and their assembly and disassembly are affected by pathophysiological conditions such as aging and disease. Disruption of protein folding in the ER lumen can activate the UPR, promoting ER membrane remodeling and MERCS formation. The UPR is mediated by three branches: IRE1α, PERK, and ATF6. These receptors are located at or near MERCS and can be either adaptive or maladaptive, depending on whether the stress is transient or sustained. Adaptive UPR signaling via MERCS can increase mitochondrial calcium import, metabolism, and dynamics, while maladaptive UPR signaling can lead to excessive calcium import and activation of apoptotic pathways. Targeting UPR signaling and MERCS assembly is an attractive therapeutic approach for age-related conditions such as neurodegeneration and sarcopenia. The review highlights the emerging evidence related to the role of redox-mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, ultimately determining cell function and fate. The redox environment of the ER is closely linked to the initiation of ER stress and UPR activation. The ER has a more oxidizing environment compared to the cytosol, which facilitates thiol-disulfide exchange for correct protein folding. The redox state of the ER can also influence the activation of the UPR. The ER is the main Ca²+ store in metazoan cells, regulating Ca²+ homeostasis, which is vital for cellular function. The ER and mitochondria are linked at MERCS, facilitating the dynamic flow of information between the organelles, allowing changes in ER homeostasis to regulate mitochondrial function. Mitochondrial dynamics are regulated by the balance between biogenesis, fusion, fission, and mitophagy. The redox environment also regulates mitochondrial dynamics, with distinct ROS signatures at sites of mitochondrial fission. Disrupted mitophagy can result in the accumulation of dysfunctional mitochondria and is associated with age-related diseases. Mitochondrial stress can activate the UPRmt, particularly ATF5, to resolve proteotoxic and oxidative stress. The redox environment of mitochondria is crucial for their function, as mitochondrial respiration generates ATP but can also result in ROS generation. Mitochondrial ROS generation has been identified as a major cause of oxidative damage in conditions such as ischemia. The redox environment of the ER and mitochondria is essential for maintaining cellular homeostasis and regulating inter-organelle communication. The regulation of