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To bridge this gap, we developed conditional transgenic models targeting the mitochondrial complex I subunit\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    in the retina. Broad deletion of\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    in the retina resulted in vision loss, progressive RGC degeneration, and pronounced immune activation before overt RGC death. Strikingly, depletion of myeloid cells significantly preserved RGCs, demonstrating that inflammation is not simply a downstream consequence but a participant in the degeneration process. To further distinguish between intrinsic and extrinsic mechanisms, we generated a mosaic model in which only subsets of retinal cells lacked\n                    <jats:italic>Ndufs4<\/jats:italic>\n                    . In this paradigm, the degeneration first appeared selectively in mutant regions, suggesting that mitochondrial impairment within RGCs is necessary to initiate vulnerability. At later stages, however, the degeneration extended beyond mutant territories, highly suggestive of a propagation through non-cell autonomous processes. Together, these findings support a model in which mitochondrial dysfunction creates the conditions for neuronal vulnerability, while immune responses govern the timing and extent of cell loss. This framework explains the consistent co-occurrence of metabolic deficits and neuroinflammation in optic neuropathies and highlights the importance of their interactions in disease progression. By clarifying the intersection of intrinsic and extrinsic mechanisms, this work advances our understanding of RGC degeneration and provides a conceptual basis for deciphering pathogenic processes across diverse optic neuropathies.\n                  <\/jats:p>","DOI":"10.1186\/s12974-026-03707-4","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:24:53Z","timestamp":1770337493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-intrinsic vulnerability and immune activation cooperate to drive degeneration in a mitochondrial complex I deficiency model of optic neuropathy"],"prefix":"10.1186","volume":"23","author":[{"given":"Daniela","family":"Santamar\u00eda-Mu\u00f1oz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raenier V.","family":"Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda R.","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Garc\u00eda-Llorca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan","family":"Marsh-Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek S.","family":"Welsbie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Marsh-Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisenda","family":"Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Quintana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Sim\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"La Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"3707_CR1","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1093\/brain\/awae324","volume":"148","author":"Y Zheng","year":"2025","unstructured":"Zheng Y, Wang P, Li S, Long Y, Jiang Y, Guo D, Jia X, Liu M, Zeng Y, Xiao X, et al. 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