{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T03:58:49Z","timestamp":1771732729884,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,2]],"date-time":"2022-10-02T00:00:00Z","timestamp":1664668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"publisher","award":["PJT-162396"],"award-info":[{"award-number":["PJT-162396"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canada Research Chairs","award":["PJT-162396"],"award-info":[{"award-number":["PJT-162396"]}]},{"name":"Canadian Foundation for Innovation","award":["PJT-162396"],"award-info":[{"award-number":["PJT-162396"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Leber hereditary optic neuropathy (LHON) is a rare syndrome that results in vision loss. A necessary but not sufficient condition for its onset is the existence of known mitochondrial DNA mutations that affect complex I biomolecular structure. Cybrids with LHON mutations generate higher rates of reactive oxygen species (ROS). This study models how ROS, particularly H2O2, could signal and execute the axonal degeneration process that underlies LHON. We modeled and explored several hypotheses regarding the influence of H2O2 on the dynamics of propagation of axonal degeneration in LHON. Zonal oxidative stress, corresponding to H2O2 gradients, correlated with the morphology of injury exhibited in the LHON pathology. If the axonal membrane is highly permeable to H2O2 and oxidative stress induces larger production of H2O2, small injuries could trigger cascading failures of neighboring axons. The cellular interdependence created by H2O2 diffusion, and the gradients created by tissue variations in H2O2 production and scavenging, result in injury patterns and surviving axonal loss distributions similar to LHON tissue samples. Specifically, axonal degeneration starts in the temporal optic nerve, where larger groups of small diameter fibers are located and propagates from that region. These findings correlate well with clinical observations of central loss of visual field, visual acuity, and color vision in LHON, and may serve as an in silico platform for modeling the mechanism of action for new therapeutics.<\/jats:p>","DOI":"10.3390\/biom12101411","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:07:43Z","timestamp":1665187663000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Modeling Reactive Oxygen Species-Induced Axonal Loss in Leber Hereditary Optic Neuropathy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1415-1259","authenticated-orcid":false,"given":"Darius W.","family":"Lambiri","sequence":"first","affiliation":[{"name":"Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard A.","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, McGill University, Montreal, QC H4A 3S5, Canada"},{"name":"Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.3201231","article-title":"Mitochondrial DNA mutation associated with Leber\u2019s hereditary optic neuropathy","volume":"242","author":"Wallace","year":"1988","journal-title":"Science"},{"key":"ref_2","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Mirzaa, G.M., and Amemiya, A. 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