title: Respiratory Chain Complex Disorganization Impairs Mitochondrial and Cellular Integrity: Phenotypic Variation in Cytochrome c Oxidase Deficiency.
abstract: The relationships between the molecular abnormalities in mitochondrial respiratory chain complexes and their negative contributions to mitochondrial and cellular functions have been proved to be essential for better understandings in mitochondrial medicine. Herein, we established the method to identify disease phenotypic differences among patients with muscle histopathological cytochrome c oxidase (COX) deficiency, as one of the representative clinical features in mitochondrial diseases, by using patients' myoblasts that are derived from biopsied skeletal muscle tissues. We identified two obviously different severities in molecular diagnostic criteria of COX deficiency among patients: structurally stable, but functionally mild/moderate defect and severe functional defect with the disrupted COX holoenzyme structure. COX holoenzyme disorganization actually triggered several mitochondrial dysfunctions, including the decreased ATP level, the increased oxidative stress level, and the damaged membrane potential level, all of which lead to the deteriorated cellular growth, the accelerated cellular senescence, and the induced apoptotic cell death. Our cell-based in vitro diagnostic approaches would be widely applicable to understanding patient-specific pathomechanism in various types of mitochondrial diseases, including other respiratory chain complex deficiencies and other mitochondrial metabolic enzyme deficiencies.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan. Electronic address: hideyuki@ncnp.go.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan; Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan. Electronic address: goto@ncnp.go.jp.
authors.forename: Yu-Ichi
authors.initials: YI
authors.lastname: Goto
mesh_terms: D030401:Cytochrome-c Oxidase Deficiency / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D020035:Holoenzymes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020035:Holoenzymes; D012333:RNA, Messenger; D003576:Electron Transport Complex IV