Pathological and therapeutic mechanisms in CoQ deficiency: the role of the proteins involved in the Q-Junction

Zusammenfassung

Mitochondria are present in most cell types. Structurally, mitochondria have two phospholipid membranes that define four biochemically distinct compartments: the outer membrane, the intermembrane space, the inner membrane and the mitochondrial matrix. Mitochondria perform a very wide range of functions and are vital in the integration of several cellular metabolic processes, most of them converging in energy production through the oxidative phosphorylation (OXPHOS). In the OXPHOS system, coenzyme Q (CoQ) is a unique electron carrier that transfer electrons from complex I and complex II to complex III, as well as from other mitochondrial enzymes, such as the electron transfer flavoprotein (ETF), the dihydroorotate dehydrogenase (DHODH), the mitochondrial glycerol-3-phosphate dehydrogenase (G3PDH or GPD2), the choline dehydrogenase (CHDH), the proline dehydrogenase (PRODH) and the sulfide:quinone oxidoreductase (SQOR). Any mitochondrial dysfunction can trigger a wide variety of pathologies, including primary mitochondrial diseases. These disorders are clinically diverse and can manifest in the neonatal phase, childhood or adulthood. This clinical heterogeneity suggests that multiple pathogenic and adaptive mechanisms are involved in the clinical manifestations of mitochondrial diseases. Recently, the remodeling of folate cycle, and its link to H2S and nucleotides metabolism, have been proposed as novel mechanisms contributing to the pathophysiological features of mitochondrial diseases. Currently, there is no available treatment for most of the mitochondrial disorders, so the therapeutic option is usually limited to palliative cares. In general, CoQ10 supplementation is recommended for patients with mitochondrial disorders or other diseases with secondary mitochondrial dysfunction, and clinical improvements have been reported in some cases, but others do not show any positive response. CoQ levels can be severely reduced in a group of mitochondrial disorders known as CoQ deficiencies. The identification of the genetic defect in CoQ deficiency is essential to differentiate primary forms, due to mutations in COQ genes, from secondary forms, due to mutations in genes not directly involved in the biosynthesis of CoQ or to not-genetic factors. The identification of common pathogenic pathways for all patients is complex due to the heterogeneity in clinical presentation, age of onset and severity of the disease. The conventional treatment for CoQ deficiency is the exogenous supplementation of high doses of CoQ10. However, this treatment has limited efficiency, especially in patients with neurological symptoms. The failure of CoQ10 therapy could be explained by the low absorption and bioavailability of exogenous CoQ10, limiting the dose that access to the affected tissues. Moreover, CoQ10 supplementation does not reduce the accumulation of intermediate metabolites or improve the endogenous biosynthesis of CoQ, although it can partially rescue the levels of SQOR in in vivo models. To overcome the disadvantages of classical therapy, new therapeutic strategies based on the use of structural analogs of the CoQ precursor 4-hydroxybenzoic acid (4-HB) has been developed. 4-HB analogs seem to modulate CoQ biosynthesis but they have limitations in rescuing SQOR levels. In the Coq9R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of the 4-HB analog, vanillic acid (VA). VA rescued the phenotypic, morphological and histopathological signs of the encephalopathy, leading to a significant increase in the survival. VA and other 4-HB analog, the b-resorcylic acid (b-RA), partially decrease the DMQ/CoQ ratio in peripheral tissues and normalize the mitochondrial proteome and metabolism related with the CoQ-linked proteins in the Qjunction in Coq9R239X mice. Specifically, the levels of PRODH, ETFDH, DHODH and CHDH are increased in the context of CoQ deficiency and normalized by the treatment with 4-HB analogs. Moreover, β-RA and VA also normalize the serum levels of acylcarnitines and some other metabolites and proteins that have the potential to be used as biomarkers to follow the progression of the disease and the response to treatments in CoQ deficiency. Additionally, here we showed that the supplementation with CoQ10 in CoQ or Complex I deficiency, induces the overexpression of SQOR, one component of the Q-junction and the first enzyme of the mitochondrial H2S oxidation pathway, leading to a downregulation of CBS and CSE, enzymes from the transsulfuration pathway. These changes are independent of sulfur aminoacids availability. The modulation of sulfide metabolism induced by CoQ10 causes the adaptation of metabolic pathways closely connected to the transsulfuration pathway and unbalanced in a variety of models of mitochondrial diseases, such as the serine biosynthesis, the folate cycle and the nucleotides metabolism. Finally, the co-administration of CoQ10 and VA in vitro leads to synergic effects in CoQ deficiency. Collectively, this work contributes to advance in the knowledge about the cellular functions of CoQ, the metabolic consequences of CoQ deficiency and the therapeutic potential of 4-HB analogs.