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: Laura García-Corzo, Marta Luna-Sánchez, Carolina Doerrier, José A García, Adela Guarás, Rebeca Acín-Pérez, Javier Bullejos-Peregrín, Ana López, Germaine Escames, José A Enríquez, Darío Acuña-Castroviejo, Luis C López
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 6 Pg. 1233-48 (Mar 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23255162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ubiquinone
• Adenosine Diphosphate
• Adenosine Triphosphate
• Electron Transport Complex I
• ubiquinone 9

Topics

• Adenosine Diphosphate (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Brain (metabolism)
• Electron Transport Complex I (genetics, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Encephalomyopathies (enzymology, genetics)
• Ubiquinone (deficiency, genetics, metabolism)