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Hum Mol Genet. 2013 Mar 15;22(6):1233-48. doi: 10.1093/hmg/dds530. Epub 2012 Dec 18.

Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency.

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  • 1Instituto de Biotecnologı´a, Centro de Investigacio´n Biome´dica, Parque Tecnolo´gico de Ciencias de la Salud, Armilla, Granada, Spain.

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.

PMID:
23255162
[PubMed - indexed for MEDLINE]
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