{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:26:59Z","timestamp":1787286419446,"version":"build-2736575974"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FONDECYT"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>\n                    Lameness in dairy cattle, driven by joint inflammation, involves fibroblast-like synoviocytes (FLS) that produce inflammatory mediators and reactive oxygen species (ROS). Tumor necrosis factor alpha (TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    ) has been proposed as an early systemic inflammatory marker that precedes and accompanies the development of lameness in transition cows. TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    signaling promotes ROS production and amplifies the inflammatory response. However, the role of mitochondrial ROS (mtROS) in regulating pro-inflammatory gene expression, particularly in bovine joint inflammation, remains to be elucidated. In this study, we investigated the role of mtROS in TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -stimulated bovine FLS. Using mitochondrial complex inhibitors, complexes I and III were identified as major contributors to mtROS generation. Antioxidants, such as N-acetyl-L-cysteine (NAC) and Mito-Tempo, suppress TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -induced expression of IL-6, IL-8, and IL-1\u03b2, with NAC showing broader efficacy in inhibiting COX-2 expression, implicating both cytosolic and mitochondrial ROS in the inflammatory response. TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    increased the lactate\/pyruvate ratio and the uptake of the fluorescent D-glucose analog 2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), suggesting an increase in glucose metabolism and a shift toward aerobic glycolysis. TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -induced NOX2 expression was reduced by NAC and Mito-Tempo, thereby linking cytosolic ROS to inflammatory amplification. Mitochondrial networks dynamically shifted from a \u201cnetworked\u201d to \u201cfragmented\u201d phenotype after TNF-\n                    <jats:italic>\u03b1<\/jats:italic>\n                    exposure, accompanied by transient depolarization. Computational classification (UMAP\/K-means) confirmed the morphological alterations. These findings demonstrate that mtROS and metabolic rewiring synergistically drive bovine synovial inflammation, highlighting mitochondrial dysfunction as a potential therapeutic target for joint inflammation-associated lameness.\n                  <\/jats:p>","DOI":"10.3389\/fvets.2026.1869964","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:22:43Z","timestamp":1787286163000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor necrosis factor alpha triggers mitochondrial dysfunction and ROS-driven cytokine amplification in bovine fibroblast-like synoviocytes"],"prefix":"10.3389","volume":"13","author":[{"given":"Natalia Andrea","family":"Godoy","sequence":"first","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Gallastegui","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biophysics, Faculty of Medicine, Institute of Physiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Vel\u00e1squez","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Teuber","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Brauchi","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biophysics, Faculty of Medicine, Institute of Physiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Quiroga","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Moran","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Ang\u00e9lica","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Hancke","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Agust\u00edn","family":"Burgos","sequence":"additional","affiliation":[{"name":"Laboratory of Inflammation Pharmacology and Immunometabolism, Faculty of Veterinary Sciences, Institute of Pharmacology and Morphophysiology, Universidad Austral de Chile","place":["Valdivia, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.prevetmed.2016.09.006","article-title":"Lameness in dairy heifers; impacts of hoof lesions present around first calving on future lameness, milk yield and culling risk","volume":"133","author":"Randall","year":"2016","journal-title":"Prev Vet Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/rda.14210","article-title":"The negative impact of lameness on dairy cow 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