{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:55:52Z","timestamp":1789131352821,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T00:00:00Z","timestamp":1587686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["CG 2013 and CG 2017"],"award-info":[{"award-number":["CG 2013 and CG 2017"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004327","name":"SingHealth Foundation","doi-asserted-by":"publisher","award":["Proteomics core facility"],"award-info":[{"award-number":["Proteomics core facility"]}],"id":[{"id":"10.13039\/501100004327","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leber\u2019s hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p &lt; 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33\/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18\/79) were involved in energetic metabolism, 31% (24\/79) exhibited catalytic activity, 73% (58\/79) showed various non-mitochondrial localizations, and 38% (30\/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP\/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies.<\/jats:p>","DOI":"10.3390\/ijms21083027","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T11:42:14Z","timestamp":1587728534000},"page":"3027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Increased Protein S-Glutathionylation in Leber\u2019s Hereditary Optic Neuropathy (LHON)"],"prefix":"10.3390","volume":"21","author":[{"given":"Lei","family":"Zhou","sequence":"first","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Research Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James Chun Yip","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Chupin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biochimie et G\u00e9n\u00e9tique, Centre Hospitalier Universitaire, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-8121","authenticated-orcid":false,"given":"Na\u00efg","family":"Gueguen","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biochimie et G\u00e9n\u00e9tique, Centre Hospitalier Universitaire, 49933 Angers, France"},{"name":"Unit\u00e9 Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1083, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Desquiret-Dumas","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biochimie et G\u00e9n\u00e9tique, Centre Hospitalier Universitaire, 49933 Angers, France"},{"name":"Unit\u00e9 Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1083, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew Kwan","family":"Koh","sequence":"additional","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Li","sequence":"additional","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Atomistic Simulations and Design in Biology, Bioinformatics Institute, 30 Biopolis Street, #07\u201301 Matrix, Singapore 138671, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gao","sequence":"additional","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Statistics and Applied Probability, Faculty of Science, National University of Singapore, Singapore 117546, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra","family":"Verma","sequence":"additional","affiliation":[{"name":"Atomistic Simulations and Design in Biology, Bioinformatics Institute, 30 Biopolis Street, #07\u201301 Matrix, Singapore 138671, Singapore"},{"name":"Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore 117558, Singpaore"},{"name":"School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger W","family":"Beuerman","sequence":"additional","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"},{"name":"Ophthalmology and Visual Sciences Academic Clinical Research Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Chun Yong","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore"},{"name":"Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Milea","sequence":"additional","affiliation":[{"name":"Ocular Proteomics, Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"},{"name":"D\u00e9partement d\u2019Ophtalmologie, Centre Hospitalier Universitaire, 49933 Angers, France"},{"name":"Neuro-Ophthalmology Department, Singapore National Eye Centre, Singapore 168751, Singpaore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-4608","authenticated-orcid":false,"given":"Pascal","family":"Reynier","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biochimie et G\u00e9n\u00e9tique, Centre Hospitalier Universitaire, 49933 Angers, France"},{"name":"Unit\u00e9 Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) U1083, Universit\u00e9 d\u2019Angers, 49933 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.5301\/ejo.5000055","article-title":"Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in 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