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This review examines the mechanisms by which heat stress induces leukocyte mitochondrial dysfunction and its downstream effects on immunity, coagulation, and organ integrity. Exposure to heat stress activates leukocytes through damage-associated molecular patterns (DAMPs), triggering the release of proinflammatory cytokines, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). These responses disrupt endothelial integrity, promote microvascular thrombosis, and contribute to the development of disseminated intravascular coagulation (DIC). Prolonged heat exposure further shifts the immune landscape toward immunosuppression, marked by monocyte deactivation and lymphocyte apoptosis. Mitochondrial dysfunction is central to this biphasic immune response. Heat stress reduces mitochondrial membrane potential, increases ROS production, and promotes the release of mitochondrial DNA and cytochrome c, amplifying inflammation and initiating cell death pathways, including apoptosis, pyroptosis, and ferroptosis. Biomarkers such as reduced mitochondrial membrane potential (\u0394\u03a8m), elevated mitochondrial ROS, cytochrome c, circulating mitochondrial DNA (mtDNA), and altered expression of mitophagy regulators (e.g., PINK1 and Parkin) provide insights into mitochondrial integrity and function in leukocytes. In addition to immune disruption, mitochondrial injury exacerbates coagulation abnormalities by promoting platelet activation and endothelial dysfunction, fostering a prothrombotic environment. In the microcirculation, leukocyte adhesion, NET formation, and endothelial damage create a self-amplifying cycle of ischemia and inflammation, ultimately leading to organ dysfunction, including hepatic failure, acute kidney injury, acute lung injury, and gastrointestinal barrier breakdown. Therapeutic strategies aimed at preserving mitochondrial function include antioxidants (e.g., N-acetylcysteine and MitoQ), mitochondrial biogenesis inducers (e.g., PGC-1\u03b1 activators), and mitophagy enhancers. Understanding the central role of leukocyte mitochondrial damage in heat stress provides a foundation for the development of targeted diagnostics and interventions to prevent organ failure and improve clinical outcomes.<\/jats:p>","DOI":"10.1186\/s40560-025-00832-9","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:33:48Z","timestamp":1762252428000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Heat stress-induced mitochondrial damage and its impact on leukocyte function"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-4088","authenticated-orcid":false,"given":"Toshiaki","family":"Iba","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0895-6800","authenticated-orcid":false,"given":"Julie","family":"Helms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0824-7406","authenticated-orcid":false,"given":"Isao","family":"Nagaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4859-4747","authenticated-orcid":false,"given":"Ricard","family":"Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3766-4962","authenticated-orcid":false,"given":"Jerrold H.","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"issue":"16","key":"832_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11164821","volume":"11","author":"T Iba","year":"2022","unstructured":"Iba T, Sawada T, Kondo Y, Kondo K, Levy JH. 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