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Although UPRmt 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 UPRmt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPRmt activation triggered by diverse insults and highlight how UPRmt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPRmt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPRmt 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 UPRmt 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 UPRmt 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 UPRmt 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.<\/jats:p>","DOI":"10.1093\/burnst\/tkag037","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T11:40:25Z","timestamp":1779277225000},"source":"Crossref","is-referenced-by-count":1,"title":["Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts"],"prefix":"10.1093","volume":"14","author":[{"given":"Yanmin","family":"Xin","sequence":"first","affiliation":[{"name":"GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong\u2013Hong Kong\u2013Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 1 Xinzao Road, Xinzao Town, Panyu District, Guangzhou , Guangdong 511436,","place":["China"]},{"name":"Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Huangpu District, Guangzhou, Guangdong 510530 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"He","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Huangpu District, Guangzhou, Guangdong 510530 ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , No. 1 East Yanqi Lake Road, Huairou District, Beijing , 101408,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7060-8204","authenticated-orcid":false,"given":"Xingguo","family":"Liu","sequence":"additional","affiliation":[{"name":"GMU-GIBH Joint School of Life Sciences, State Key Lab of Respiratory Disease, The Guangdong\u2013Hong Kong\u2013Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 1 Xinzao Road, Xinzao Town, Panyu District, Guangzhou , Guangdong 511436,","place":["China"]},{"name":"Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , No. 190 Kaiyuan Avenue, Huangpu District, Guangzhou, Guangdong 510530 ,","place":["China"]},{"name":"Centre for Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences , Science Park West Avenue, Hong Kong Science Park, Pak Shek Kok, New Territories, Hong Kong, SAR , 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