{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:01:42Z","timestamp":1789732902436,"version":"4.0.1"},"reference-count":120,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"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>Leber hereditary optic neuropathy (LHON) is a mitochondrial disease caused primarily by pathogenic mitochondrial DNA (mtDNA) variants that impair respiratory chain complex I function. Although bioenergetic failure, oxidative stress, and retinal ganglion cell degeneration are central features of disease pathogenesis, these mechanisms do not fully explain the incomplete penetrance, male predominance, and marked clinical heterogeneity observed in LHON. Emerging evidence suggests that mitochondrial dysfunction can also trigger sterile inflammatory responses through the release of mitochondrial damage-associated molecular patterns (DAMPs), including mtDNA and reactive oxygen species, and through impaired mitophagic clearance. These signals activate innate immune pathways, including cGAS-STING, TLR9, and the NLRP3 inflammasome, potentially contributing to neuroinflammation, glial activation, and secondary neuronal injury. The relevance of immune signaling has gained further attention with the development of AAV-based gene therapies for LHON, where treatment-associated ocular inflammation has emerged as a clinically important challenge. In this review, we examine the evidence linking mitochondrial dysfunction to innate immune activation in LHON, discuss the immunological mechanisms underlying disease progression and gene therapy-associated inflammation, and highlight emerging opportunities for biomarker development, immunomodulatory intervention, and improved therapeutic design. We propose that LHON should be viewed not only as a disorder of mitochondrial bioenergetics but also as a neuroinflammatory disease shaped by the interplay between mitochondrial stress and immune signaling.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1935135","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:03:49Z","timestamp":1789729429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sterile inflammation in LHON: mitochondrial stress, innate immune signaling, and implications for AAV gene therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Xue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]},{"name":"Bascom Palmer Eye Institute, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqin","family":"Chang","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yu","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute, University of Miami Miller School of Medicine","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.3.162","article-title":"Leber hereditary optic 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