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Their role in disease is unclear, though both have been linked to mitochondrial respiration and mitochondrial stress responses. Here, we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to motor impairment, reduced survival and compromised neuromuscular junction integrity in larval zebrafish. Compensation by Chchd10 was observed in the <jats:italic>chchd2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> model, but not by Chchd2 in the <jats:italic>chchd10<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> model. The assembly of mitochondrial respiratory chain Complex I was impaired in <jats:italic>chchd10<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> and <jats:italic>chchd2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> zebrafish larvae, but unexpectedly not in a double <jats:italic>chchd10<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> and <jats:italic>chchd2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. We observed transcriptional activation markers of the mitochondrial integrated stress response (mt\u2010ISR) in the double <jats:italic>chchd10<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> and <jats:italic>chchd2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> KO model, suggesting that this pathway is involved in the restoration of Complex I assembly in our double KO model. The data presented here demonstrates that the Complex I assembly defect in our single KO models arises independently of the mt\u2010ISR. Furthermore, this study provides evidence that both proteins are required for normal vertebrate development.<\/jats:p>","DOI":"10.1002\/dneu.22909","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T07:53:51Z","timestamp":1676620431000},"page":"54-69","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS\u2010like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response"],"prefix":"10.1002","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0544-0905","authenticated-orcid":false,"given":"Virginie","family":"Petel L\u00e9gar\u00e9","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute Faculty of Medicine McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Rampal","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute Faculty of Medicine McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J. N.","family":"Gurberg","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery Montreal Neurological Institute Faculty of Medicine McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari J.","family":"Aaltonen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Janer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne","family":"Zinman","sequence":"additional","affiliation":[{"name":"Sunnybrook Health Sciences Centre  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Shoubridge","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A. 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