{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:18:48Z","timestamp":1789525128187,"version":"build-2803163510"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Traditionally recognized as \u201ccellular powerhouses\u201d, mitochondria have gained relevance as pivotal nodes in the integration of metabolism, stress signaling, and innate immunity. In this context, the present work seeks to answer the following question: Does the continuous, exercise-induced mitochondrial stress contribute towards training of innate immune cells by promoting the generation of DAMPs such as mtDNA and succinate? Exercise can be considered as a form of controllable mitochondrial stressor. Mechanistically, the temporary release of mtDAMPs through exercise results in activation of pattern recognition receptors (NLRP3, TLR9, cGAS-STING). Subsequently, there is a metabolic reprogramming event favoring switch from oxidative phosphorylation to aerobic glycolysis along with epigenetic changes (H3K4me3, H3K27ac) priming pro-inflammatory genes for enhanced secondary response. Moderate-intensity exercise develops an immune homeostatic condition with reduced low-grade inflammation and increased reactivity, while sedentary behavior fosters chronic low-grade inflammation, and excessive high-volume exercise can temporarily reduce immune competency. Herein, we present an integrative model where exercise-induced mitochondrial stress as a physiological \u201ctraining vaccine\u201d to enhance immune surveillance via trained immunity principles. The current model helps differentiate the immune status of elite athletes from sedentary subjects and paves the way for understanding the immunological benefit of exercise prescription in infection prevention, metabolic health, and cancer immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1902029","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:23:56Z","timestamp":1783571036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity"],"prefix":"10.3389","volume":"17","author":[{"given":"Enli","family":"Xie","sequence":"first","affiliation":[{"name":"School of Sports Training, Nanjing Sport Institute","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushan","family":"He","sequence":"additional","affiliation":[{"name":"School of Sports Training, Nanjing Sport Institute","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Physical Education and Humanities, Nanjing Sport Institute","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained immunity: a memory for innate host defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: a program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2020.100897","article-title":"Immunometabolic control of trained immunity","volume":"77","author":"Riksen","year":"2021","journal-title":"Mol Aspects Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jshs.2018.09.009","article-title":"The compelling link between physical activity and the body\u2018s defense system","volume":"8","author":"Nieman","year":"2019","journal-title":"J Sport Health Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.3.1055","article-title":"Exercise and the immune system: regulation, integration, and adaptation","volume":"80","author":"Pedersen","year":"2000","journal-title":"Physiol Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3704","article-title":"Mitochondria are the powerhouses of immunity","volume":"18","author":"Mills","year":"2017","journal-title":"Nat Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.70","article-title":"A guide to immunometabolism for immunologists","volume":"16","author":"O\u2019Neill","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/nri2975","article-title":"Mitochondria in innate immune responses","volume":"11","author":"West","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.01.009","article-title":"Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis","volume":"36","author":"Shimada","year":"2012","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature08780","article-title":"Circulating mitochondrial DAMPs cause inflammatory responses to injury","volume":"464","author":"Zhang","year":"2010","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26073069","article-title":"Mitochondrial DNA in exercise-mediated innate immune responses","volume":"26","author":"Wen","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0000000000001157","article-title":"Recent advances in exercise immunometabolism: immune cell bioenergetics, muscle-immune cell interactions, and potential dietary adjuvants","volume":"28","author":"Islam","year":"2025","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiq150","article-title":"Hide and seek. 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