{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:15:25Z","timestamp":1787804125268,"version":"build-2784847793"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Paul and Evanina Bell Mackall Foundation Trust"},{"DOI":"10.13039\/100016935","name":"Lisa Dean Moseley Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016935","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-NS007413"],"award-info":[{"award-number":["T32-NS007413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35-GM134863"],"award-info":[{"award-number":["R35-GM134863"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-GM120762"],"award-info":[{"award-number":["R01-GM120762"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HD065858"],"award-info":[{"award-number":["R01-HD065858"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Will Woleben SURF1 Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression and progressive multisystem dysfunction. Here, we describe two novel surf1\u2212\/\u2212 zebrafish knockout models generated by CRISPR\/Cas9 technology. While gross larval morphology, fertility, and survival into adulthood appeared unaffected, surf1\u2212\/\u2212 mutants manifested adult-onset ocular anomalies and decreased swimming activity, as well as classical biochemical hallmarks of human SURF1 disease, including reduced complex IV expression and enzymatic activity and increased tissue lactate. surf1\u2212\/\u2212 larvae also demonstrated oxidative stress and stressor hypersensitivity to the complex IV inhibitor, azide, which exacerbated their complex IV deficiency, reduced supercomplex formation, and induced acute neurodegeneration typical of LS including brain death, impaired neuromuscular responses, reduced swimming activity, and absent heartrate. Remarkably, prophylactic treatment of surf1\u2212\/\u2212 larvae with either cysteamine bitartrate or N-acetylcysteine, but not other antioxidants, significantly improved animal resiliency to stressor-induced brain death, swimming and neuromuscular dysfunction, and loss of heartbeat. Mechanistic analyses demonstrated cysteamine bitartrate pretreatment did not improve complex IV deficiency, ATP deficiency, or increased tissue lactate but did reduce oxidative stress and restore glutathione balance in surf1\u2212\/\u2212 animals. Overall, two novel surf1\u2212\/\u2212 zebrafish models recapitulate the gross neurodegenerative and biochemical hallmarks of LS, including azide stressor hypersensitivity that was associated with glutathione deficiency and ameliorated by cysteamine bitartrate or N-acetylcysteine therapy.<\/jats:p>","DOI":"10.1093\/hmg\/ddad031","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T15:12:56Z","timestamp":1676560376000},"page":"1988-2004","source":"Crossref","is-referenced-by-count":15,"title":["<i>N<\/i>-acetylcysteine and cysteamine bitartrate prevent azide-induced neuromuscular decompensation by restoring glutathione balance in two novel <i>surf1<\/i>\n                  <i>\u2212\/\u2212<\/i> zebrafish deletion models of Leigh syndrome"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5575-4609","authenticated-orcid":false,"given":"Suraiya","family":"Haroon","sequence":"first","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"},{"name":"University of Pennsylvania Perelman School of Medicine Department of Pediatrics, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heeyong","family":"Yoon","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-1689","authenticated-orcid":false,"given":"Christoph","family":"Seiler","sequence":"additional","affiliation":[{"name":"Zebrafish Core, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Osei-Frimpong","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"He","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Scheie Eye Center, Department of Ophthalmology, Perelman School of Medicine, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohini M","family":"Nair","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Scheie Eye Center, Department of Ophthalmology, Perelman School of Medicine, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal D","family":"Mathew","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2795-9775","authenticated-orcid":false,"given":"Leonard","family":"Burg","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"Kose","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chavali R M","family":"Venkata","sequence":"additional","affiliation":[{"name":"University of Pennsylvania Scheie Eye Center, Department of Ophthalmology, Perelman School of Medicine, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-7621","authenticated-orcid":false,"given":"Vernon E","family":"Anderson","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0931-1940","authenticated-orcid":false,"given":"Eiko","family":"Nakamaru-Ogiso","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"},{"name":"University of Pennsylvania Perelman School of Medicine Department of Pediatrics, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1723-6728","authenticated-orcid":false,"given":"Marni J","family":"Falk","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA , USA"},{"name":"University of Pennsylvania Perelman School of Medicine Department of Pediatrics, , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"2023062014042798200_ref1","doi-asserted-by":"crossref","first-page":"25735","DOI":"10.1074\/jbc.M109.040295","article-title":"Surf1, associated with Leigh syndrome in humans, is a heme-binding protein in bacterial oxidase biogenesis","volume":"284","author":"Bundschuh","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2023062014042798200_ref2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1750-1172-8-96","article-title":"SURF1 deficiency: a multi-centre natural history study","volume":"8","author":"Wedatilake","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"2023062014042798200_ref3","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1093\/hmg\/ddg038","article-title":"Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice","volume":"12","author":"Agostino","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2023062014042798200_ref4","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/hmg\/ddl477","article-title":"Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice","volume":"16","author":"Dell'agnello","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2023062014042798200_ref5","doi-asserted-by":"crossref","first-page":"29235","DOI":"10.1074\/jbc.M114.602938","article-title":"Leigh syndrome in Drosophila melanogaster: morphological and biochemical characterization of Surf1 post-transcriptional silencing","volume":"289","author":"Da-Re","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2023062014042798200_ref6","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1016\/j.bbadis.2018.03.021","article-title":"SURF1 knockout cloned pigs: early onset of a severe lethal phenotype","volume":"1864","author":"Quadalti","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. basis Dis."},{"key":"2023062014042798200_ref7","first-page":"636","article-title":"A new missense mutation of 574C&gt;T in the SURF1 gene--biochemical and molecular genetic study in seven children with Leigh syndrome","volume":"141","author":"Capkov\u00e1","year":"2002","journal-title":"Cas. Lek. Cesk."},{"key":"2023062014042798200_ref8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/3804","article-title":"SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome","volume":"20","author":"Zhu","year":"1998","journal-title":"Nat. Genet."},{"key":"2023062014042798200_ref9","doi-asserted-by":"crossref","first-page":"148193","DOI":"10.1016\/j.bbabio.2020.148193","article-title":"Kinetic advantage of forming respiratory supercomplexes","volume":"1861","author":"Stuchebrukhov","year":"2020","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"2023062014042798200_ref10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.bbabio.2013.11.002","article-title":"Functional role of mitochondrial respiratory supercomplexes","volume":"1837","author":"Genova","year":"2014","journal-title":"Biochim. Biophys. 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