title: The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.
abstract: Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holocytochrome c-type synthase (HCCS)gene [corrected]. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 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-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Indrieri
authors.forename: Ivan
authors.initials: I
authors.lastname: Conte
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Chesi
authors.forename: Alessia
authors.initials: A
authors.lastname: Romano
authors.forename: Jade
authors.initials: J
authors.lastname: Quartararo
authors.forename: Rosarita
authors.initials: R
authors.lastname: Tatè
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
authors.forename: Brunella
authors.initials: B
authors.lastname: Franco
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology* / Q000201:enzymology; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D005123:Eye / Q000166:cytology* / Q000201:enzymology; D005260:Female; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008190:Lyases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008850:Microphthalmos / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009990:Oryzias / Q000235:genetics* / Q000378:metabolism
chemical_list: D029941:Fish Proteins; D045304:Cytochromes c; D053453:Caspase 9; D008190:Lyases; C031581:cytochrome C synthetase