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Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the\n                  <jats:italic>Ndufs4<\/jats:italic>\n                  (-\/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient\n                  <jats:italic>Ndufs4<\/jats:italic>\n                  (-\/-)\/\n                  <jats:italic>MyD88<\/jats:italic>\n                  (-\/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of\n                  <jats:italic>MyD88<\/jats:italic>\n                  in\n                  <jats:italic>Ndufs4<\/jats:italic>\n                  (-\/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that\n                  <jats:italic>Myd88<\/jats:italic>\n                  -mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient\n                  <jats:italic>MyD88<\/jats:italic>\n                  (-\/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.\n                <\/jats:p>","DOI":"10.64898\/2026.05.13.724988","type":"posted-content","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:40:22Z","timestamp":1779086422000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>MyD88<\/i>\n                  deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8745-9724","authenticated-orcid":false,"given":"Allison R","family":"Hanaford","sequence":"first","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizaveta A","family":"Olkhova","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Liao","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Ching","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Centre for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin","family":"Huang","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Centre for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin Shien","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Centre for 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Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"James","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mulholland","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Truong","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Coulson","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry","family":"Gibbins","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Cairns","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Dimitriou","sequence":"additional","affiliation":[{"name":"Translational Bioscience, Northumbria University, Newcastle, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Kayser","sequence":"additional","affiliation":[{"name":"Center for Integrated Brain Research, Seattle Children\u2019s Research Institute, Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany 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