Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency

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 h...

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Bibliographic Details
Published in:Human molecular genetics 2013-03, Vol.22 (6), p.1233-1248
Main Authors: García-Corzo, Laura, Luna-Sánchez, Marta, Doerrier, Carolina, García, José A, Guarás, Adela, Acín-Pérez, Rebeca, Bullejos-Peregrín, Javier, López, Ana, Escames, Germaine, Enríquez, José A, Acuña-Castroviejo, Darío, López, Luis C
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - metabolism
Adenosine Triphosphate - metabolism
Animals
Brain - metabolism
Electron Transport Complex I - genetics
Electron Transport Complex I - metabolism
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Encephalomyopathies - enzymology
Mitochondrial Encephalomyopathies - genetics
Ubiquinone - deficiency
Ubiquinone - genetics
Ubiquinone - metabolism
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/dds530