Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts

The mitochondrial unfolded protein response (UPR^mt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPR^mt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPR^mt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPR^mt activation triggered by diverse insults and highlight how UPR^mt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPR^mt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPR^mt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPR^mt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPR^mt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPR^mt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.