title: Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation.
abstract: Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the 'Mitochondrial contact site and Cristae Organizing system' (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network. Moreover, DISC1 depleted cells have decreased mitochondrial DNA (mtDNA) content and steady state levels of oxidative phosphorylation (OXPHOS) subunits. As a consequence, OXPHOS complexes and supercomplexes are partially disassembled in DISC1 knockdown cells, which suffer severe bioenergetic defects, evidenced by impaired oxygen consumption, adenosine triphosphate synthesis and mitochondrial membrane potential. Transfection of recombinant full-length human DISC1 restores MICOS complex assembly and rescues OXPHOS function, meanwhile overexpression of the DISC1 truncated form Δ597-854, known to be pathogenic, fails to rescue the bioenergetic impairment caused by DISC1 knockdown. These results should contribute to reveal DISC1 physiological function and potential pathogenic role in severe mental illnesses.
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Piñero-Martos
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ortega-Vila
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Pol-Fuster
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cisneros-Barroso
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ruiz-Guerra
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Aina
authors.initials: A
authors.lastname: Medina-Dols
authors.affiliation: Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.|Department of Genetics, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain.
authors.forename: Damián
authors.initials: D
authors.lastname: Heine-Suñer
authors.affiliation: Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.|Grup de Neurobiologia Cel·lular, Departament de Biologia, i Institut Universitari d'Investigacions en Ciències de la Salut, IUNICS, Universitat de les Illes Balears (UIB), 07122 Palma de Mallorca, Spain.
authors.forename: Jerònia
authors.initials: J
authors.lastname: Lladó
authors.affiliation: Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.|Grup de Neurobiologia Cel·lular, Departament de Biologia, i Institut Universitari d'Investigacions en Ciències de la Salut, IUNICS, Universitat de les Illes Balears (UIB), 07122 Palma de Mallorca, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Olmos
authors.affiliation: Neurobiology Laboratory, Research Unit, Hospital Universitari Son Espases, 07010 Palma de Mallorca, Spain cristofol.vives@ssib.es.|Institut d'Investigació Sanitària de Palma (IdISPa), 07010 Palma de Mallorca, Spain.
authors.forename: Cristofol
authors.initials: C
authors.lastname: Vives-Bauzà
mesh_terms: D002460:Cell Line; D018385:Centrosome / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D010085:Oxidative Phosphorylation; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C412476:DISC1 protein, human; D004272:DNA, Mitochondrial; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins