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However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non\u2010canonical mitochondrial\u2010dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X\u2010linked developmental disorder caused by mutations in the holo\u2010cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    \u2010type synthase (\n                    <jats:italic>HCCS<\/jats:italic>\n                    ) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of\n                    <jats:italic>hccs<\/jats:italic>\n                    , an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome\u2010independent caspase\u20109 activation in brain and eyes. We also show that the unconventional activation of caspase\u20109 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non\u2010canonical start\u2010up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.\n                  <\/jats:p>","DOI":"10.1002\/emmm.201201739","type":"journal-article","created":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T19:27:06Z","timestamp":1355426826000},"page":"280-293","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["The impairment of HCCS leads to MLS syndrome by activating a non\u2010canonical cell death pathway in the brain and eyes"],"prefix":"10.1038","volume":"5","author":[{"given":"Alessia","family":"Indrieri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Chesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade","family":"Quartararo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosarita","family":"Tat\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Zeviani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Goffrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Ferrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Bovolenta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunella","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,1,22]]},"reference":[{"key":"BFEMMM201201739_CR1","doi-asserted-by":"crossref","first-page":"8199","DOI":"10.1523\/JNEUROSCI.0979-08.2008","volume":"28","author":"O Anichtchik","year":"2008","unstructured":"Anichtchik O, Diekmann H, Fleming A, Roach A, Goldsmith P, Rubinsztein DC (2008) Loss of PINK1 function affects development and results in neurodegeneration in zebrafish. 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