Therapeutic potential of Ubiqsome® supplementation in contrasting atorvastatin-induced cytotoxicity in vitro and CDKL5 deficiency in vivo

Statins are the primary treatment for managing elevated cholesterol levels linked to acute cardiovascular risk. However, their use can lead to side effects, likely due to depletion of CoQ10, crucial for the mitochondrial electron transport chain and membranes antioxidant systems. We show that Atorvastatin causes cytotoxic effects in human fibroblasts by inducing oxidative stress and mitochondrial dysfunction. Supplementation with a formulated CoQ10, Ubiqsome®, in statin-treated cells considerably reduced ROS levels, OCR and the ATP/ADP ratio. Additionally, the data suggest that at high doses, off-target effects involve inhibition of mitochondrial respiratory complexes I and III, triggering reverse electron transport and ROS production at Complex I. Ubiqsome® was also tested in vivo, to ameliorate the oxidative stress related to the CDKL5 deficiency disorder (CDD), characterized by a complex and severe clinical presentation, including early-onset epilepsy, cognitive, motor, visual, and gastrointestinal impairments. Although CDD is primarily a genetic disorder affecting the brain, evidence suggests the presence of systemic abnormalities, such as a redox imbalance in plasma and skin fibroblasts derived from CDD patients, as well as in cardiac myocytes of a mouse model of CDD. To elucidate the role of oxidative stress in CDD pathophysiology, we investigated the therapeutic potential of Coenzyme Q10, known for its potent antioxidant properties, using both in vitro and in vivo models of CDD. Our findings demonstrated that CoQ10 supplementation decreased general and mitochondrial reactive oxygen species (ROS) levels and restored glutathione homeostasis in vitro, using a neuronal cell model lacking the CDKL5 gene. Notably, CoQ10 administered as Ubiqsome® provided a protective effect against lipid peroxidation and DNA damage in the heart tissue of a murine CDD model, the Cdkl5+/− female mouse, even though no alterations in CoQ content were observed in heart tissues.