{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:47:29Z","timestamp":1793051249864,"version":"4.5.0"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"ANID | Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1191770"],"award-info":[{"award-number":["1191770"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,3,21]]},"abstract":"<jats:p>\n                    Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in\n                    <jats:italic>OPA1<\/jats:italic>\n                    lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying\n                    <jats:italic>OPA1<\/jats:italic>\n                    GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied\n                    <jats:italic>OPA1<\/jats:italic>\n                    GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from\n                    <jats:italic>OPA1<\/jats:italic>\n                    GTPase (c.870+5G&gt;A and c.889C&gt;T) and GED (c.2713C&gt;T and c.2818+5G&gt;A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2207471120","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T13:38:45Z","timestamp":1678973925000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":38,"title":["<i>OPA1<\/i>\n                    disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2753-5780","authenticated-orcid":false,"given":"Benjam\u00edn","family":"Cartes-Saavedra","sequence":"first","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-5397","authenticated-orcid":false,"given":"Daniel","family":"Lagos","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-2233","authenticated-orcid":false,"given":"Josefa","family":"Macuada","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duxan","family":"Arancibia","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"},{"name":"Departamento Biom\u00e9dico, Facultad de Ciencias de la Salud, Universidad de Antofagasta, Antofagasta 1240000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-7838","authenticated-orcid":false,"given":"Florence","family":"Burt\u00e9","sequence":"additional","affiliation":[{"name":"Wellcome Trust for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7173-048X","authenticated-orcid":false,"given":"Marcela K.","family":"Sj\u00f6berg-Herrera","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-2770","authenticated-orcid":false,"given":"Mar\u00eda Estela","family":"Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Departamento Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-170X","authenticated-orcid":false,"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"John Van Geest Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7847-9320","authenticated-orcid":false,"given":"Patrick","family":"Yu-Wai-Man","sequence":"additional","affiliation":[{"name":"John Van Geest Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, UK"},{"name":"Mitochondrial Research Council Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK"},{"name":"Cambridge Eye Unit, Addenbrooke\u2019s Hospital, Cambridge University Hospitals, Cambridge CB2 0QQ, UK"},{"name":"University College London Institute of Ophthalmology, University College London, London EC1V 9EL, UK"},{"name":"Moorfields Eye Hospital National Health Service Foundation Trust, London EC1V 2PD, 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