title: Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency.
abstract: Coenzyme Q10 (CoQ(10)) or ubiquinone is a well-known component of the mitochondrial respiratory chain. In humans, CoQ(10) deficiency causes a mitochondrial syndrome with an unexplained variability in the clinical presentations. To try to understand this heterogeneity in the clinical phenotypes, we have generated a Coq9 Knockin (R239X) mouse model. The lack of a functional Coq9 protein in homozygous Coq9 mutant (Coq9(X/X)) mice causes a severe reduction in the Coq7 protein and, as consequence, a widespread CoQ deficiency and accumulation of demethoxyubiquinone. The deficit in CoQ induces a brain-specific impairment of mitochondrial bioenergetics performance, a reduction in respiratory control ratio, ATP levels and ATP/ADP ratio and specific loss of respiratory complex I. These effects lead to neuronal death and demyelinization with severe vacuolization and astrogliosis in the brain of Coq9(X/X) mice that consequently die between 3 and 6 months of age. These results suggest that the instability of mitochondrial complex I in the brain, as a primary event, triggers the development of mitochondrial encephalomyopathy associated with CoQ deficiency.
authors.affiliation: Instituto de Biotecnologı´a, Centro de Investigacio´n Biome´dica, Parque Tecnolo´gico de Ciencias de la Salud, Armilla, Granada, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Corzo
authors.forename: Marta
authors.initials: M
authors.lastname: Luna-Sánchez
authors.forename: Carolina
authors.initials: C
authors.lastname: Doerrier
authors.forename: José A
authors.initials: JA
authors.lastname: García
authors.forename: Adela
authors.initials: A
authors.lastname: Guarás
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.forename: Javier
authors.initials: J
authors.lastname: Bullejos-Peregrín
authors.forename: Ana
authors.initials: A
authors.lastname: López
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
authors.forename: José A
authors.initials: JA
authors.lastname: Enríquez
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology* / Q000235:genetics; D014451:Ubiquinone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014451:Ubiquinone; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; C030571:ubiquinone 9