This mutation is homologue to the human R244X mutation (Duncan et al, 2009). To better understand the pathophysiologic consequences of primary CoQ 10 deficiency, we recently generated a mouse model carrying a homozygous mutation in Coq9 gene (R239X, Coq9 R239X). The causes of this clinical variability are unknown, and it is difficult to explain why mutations in the same gene may cause different phenotypes, for example, mutations in COQ2 and COQ6 have been associated with isolated nephropathy or multisystemic disease (Quinzii et al, 2006 Diomedi-Camassei et al, 2007 Heeringa et al, 2011 Jakobs et al, 2013), due to the limited number of patients described. Moreover, mutations in COQ2 have been recently reported in Japanese patients with multiple system atrophy (Multiple-System Atrophy Research, 2013). Mutations in CoQ biosynthetic genes produce primary CoQ 10 deficiency, a mitochondrial syndrome with five major clinical presentations: (i) encephalomyopathy with brain involvement and recurrent myoglobinuria (ii) infantile multisystem disorder with encephalopathy usually associated with nephropathy and variable involvement of other organs (iii) ataxic syndrome with cerebellar atrophy (iv) isolated myopathy and (v) steroid-resistant nephrotic syndrome (Emmanuele et al, 2012). However, there is no proof of the existence of a multiprotein complex for CoQ biosynthesis in mammals. This organization would allow channeling of labile/reactive intermediates, enhance catalytic efficiency, and provide a mechanism for coordinative regulation of components (Tran & Clarke, 2007). Moreover, several studies have shown evidence that, in yeast, the enzymes required for CoQ biosynthesis are organized in a multiprotein complex. Other proteins are thought to have regulatory functions in the CoQ biosynthetic pathway: (i) COQ9 is essential for the function of COQ7, an enzyme that catalyzes the hydroxylation of demethoxyubiquinone to produce 5-hydroxyquinone (Garcia-Corzo et al, 2013) (ii) ADCK3 and ADCK4 regulate other CoQ biosynthetic proteins by their kinase activities (Tran & Clarke, 2007) and (iii) PTC7 regulates the activity of COQ7 by its phosphatase activity (Martin-Montalvo et al, 2013). Then, 4-para-hydroxybenzoate:polyprenyl transferase, encoded by Coq2, mediates the conjugation of the aromatic ring precursor, 4-HB, to the side chain, while five other enzymes, encoded by Coq3 to Coq7, reside in the mitochondrial inner membrane and modify the quinone ring of CoQ (Supplementary Fig S1) (Tran & Clarke, 2007). While the quinone ring is derived from tyrosine or phenylalanine, the isoprenoid side chain is produced by addition of isopentenyl diphosphate molecules to farnesyl diphosphate or geranylgeranyl diphosphate in multiple steps catalyzed by polyprenyl diphosphate synthase (PDSS1–PDSS2). Its endogenous biosynthesis occurs ubiquitously in the mitochondria and starts with the formation of a 4-hydroxybenzoate (4-HB) head group and a lipophilic polyisoprenoid tail. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype–phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.Ĭoenzyme Q (CoQ) is an essential molecule for mitochondrial ATP synthesis and other metabolic processes (Turunen et al, 2004 Garcia-Corzo et al, 2013). 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 Coq9 R239X mice destabilizes the CoQ multiprotein complex. In contrast, Coq9 Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. Coq9 R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. Here, we compare two mouse models with a genetic modification in Coq9 gene ( Coq9 Q95X and Coq9 R239X), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). The disease has been associated with five major phenotypes, but a genotype–phenotype correlation is unclear. Primary coenzyme Q 10 (CoQ 10) deficiency is due to mutations in genes involved in CoQ biosynthesis.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |