Treatment effect of coenzyme Q₁₀ and an antioxidant cocktail in fibroblasts of patients with Sanfilippo disease

Abstract

Coenzyme Q10 (CoQ10) plays a key role in the exchange of electrons in lysosomal membrane, which contributes to protons' translocation into the lumen and to the acidification of intra-lysosomal medium, which is essential for the proteolytic function of hydrolases responsible -when deficient- of a wide range of inherited lysosomal diseases such as Sanfilippo syndromes. Our aim was to evaluate whether treatment with CoQ10 or with an antioxidant cocktail (α-tocopherol, N-acetylcysteine and α-lipoic acid) were able to ameliorate the biochemical phenotype in cultured fibroblasts of Sanfilippo patients. Basal CoQ10 was analyzed in fibroblasts and Sanfilippo A patients showed decreased basal levels. However, no dysfunction in the CoQ10 biosynthesis pathways was found, revealing for the first time a secondary CoQ10 deficiency in Sanfilippo A fibroblasts. Cultured fibroblasts from five patients affected by Sanfilippo A and B diseases were treated with CoQ10 and an antioxidant cocktail. Upon CoQ10 treatment, none of the Sanfilippo A fibroblasts increased their residual enzymatic activity, but the two Sanfilippo B cell lines showed a statistically significant increase of their residual activity. The antioxidant treatment had no effect on the residual activity in all tested cell lines. Moreover, one Sanfilippo A and two Sanfilippo B fibroblasts showed a statistically significant reduction of glycosaminoglycans accumulation both, after 50 μmol/L CoQ10 and antioxidant treatment. Fibroblasts responsive to treatment enhanced their exocytosis levels. Our results are encouraging as some cellular alterations observed in Sanfilippo syndrome can be partially restored by CoQ10 or other antioxidant treatment in some patients.

Coenzyme Q10 and Pyridoxal Phosphate Deficiency Is a Common Feature in Mucopolysaccharidosis Type III

“…Total cholesterol values were normal, suggesting that the cause of such deficiency is probably unrelated to impaired cholesterol biosynthesis (and consequently CoQ biosynthesis). This statement would be supported by the data of Matalonga et al, who demonstrated a normal CoQ biosynthesis rate in cultured skin fibroblast from MPS patients (Matalonga et al 2014). Plasma CoQ values depend on dietary sources (around 20% of total CoQ) and liver biosynthesis, but dietary CoQ deficiency is unlikely considering the adequate nutritional status of our patients and the normality of most of the other vitamins and trace elements analyzed.…”

“…Increased CoQ consumption may also be a factor explaining this deficiency, since some authors suggested the possible involvement of the reactive oxygen species in the MPS type IIIB disease pathogenesis (Villani et al 2009). Recently a positive effect has been observed in cultured fibroblasts from Sanfilippo A and B treated with CoQ and other antioxidants (Matalonga et al 2014). Moreover, since CoQ participates in tocopherol recycling (Navas et al 2007), the significantly lower median tocopherol values observed in our MPS patients when compared with age-matched controls might be related with the CoQ deficiency.…”

Mitochondrial dysfunction associated with glucocerebrosidase deficiency

“…Changes in lipid/sterol metabolism as a result of GCase inhibition may impact on the biosynthesis of CoQ 10 ( Hargreaves, 2014 ). Alternatively, CoQ10 is also known to play a role in the proton translocation across the lysosomal membrane ( Matalonga et al, 2014 ), and the lysosomal accumulation of substrate in GD may have an effect on the lysosomal pool of CoQ 10 . Despite the uncertainty, it is becoming increasingly clear that treatment with CoQ 10 or analogues such as MitoQ can partially reverse the mitochondrial dysfunction and oxidative stress observed in cell models of GD and other lysosomal storage disorders ( De la Mata et al, 2015 , Matalonga et al, 2014 , Osellame et al, 2013 ).…”

Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease

“…Likewise, as mitochondrial dysfunction and/or impaired mitochondria elimination may be associated to alterations of lysosome-dependent processes, coenzyme Q 10 (CoQ), an antioxidant and mitochondrial energizer, is currently considered as a potential experimental drug for the treatment of neurodegenerative diseases in general 24 and lysosomal diseases in particular 25 . We conceived that addressing both mutant GCase rescuing by NAdBT-AIJ as PC and mitochondrial function by CoQ might lead to beneficial synergies.…”