1 research outputs found
The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene
Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotypeâphenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9Q95X and Coq9R239X), and their responses to 2,4âdihydroxybenzoic acid (2,4âdiHB). Coq9R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4âdiHB increasing CoQ levels. In contrast, Coq9Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and lateâonset mild mitochondrial myopathy, which does not respond to 2,4âdiHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9R239X mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotypeâphenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.This work was supported by grants from the Marie
Curie International Reintegration Grant Programme (COQMITMEL-266691 to
LCL) within the Seventh European Community Framework Programme, from
Ministerio de EconomĂa y Competitividad, Spain (SAF2009-08315 and
SAF2013-47761-R to LCL), from the ConsejerĂa de EconomĂa, InnovaciĂłn,
Ciencia y Empleo, Junta de AndalucĂa (P10-CTS-6133 to LCL), and from the
âCEIBioTicâ (20F12/1 to LCL). MLS is a predoctral fellow from the ConsejerĂa
de EconomĂa, InnovaciĂłn, Ciencia y Empleo, Junta de AndalucĂa. LCL is
supported by the âRamĂłn y Cajalâ National Programme, Ministerio de
EconomĂa y Competitividad, Spain (RYC-2011-07643). MAT is supported by a
predoctoral grant from the University of Granada. EJC is supported by the Research Program of the University of Granada. CMQ is supported by
NICHD Grants 5K23 HDO65871-05 and P01 HD080642-01, and by a MDA
grant. The proteomic analysis was performed in the CSIC/UAB Proteomics
Facility of IIBB-CSIC that belongs to ProteoRed, PRB2-ISCIII, supported by
Grant PT13/0001