Evaluation of the effects of coenzyme Q10 and succinate in a rotenone-induced complex I deficient rat model

Abstract

Disorders of the mitochondrial respiratory chain have an incidence ranging from 1 in 2,000 to 1 in 5,000, with the most frequent of these cytopathies resulting from causative alterations within mitochondrial complex I, the first enzyme of the respiratory chain. The biochemical consequences of a complex I deficiency include, amongst others, failure to oxidise reduced nicotinamide adenine dinucleotide (NADH), impairment of the Krebs cycle, elevated blood lactate, lowered adenosine triphosphate (ATP) generation and an increased production of reactive oxygen species (ROS). The aim of the investigation was to evaluate the effects of CoQ10 and succinate in a rotenone-induced animal model. Sprague Dawley rats were dosed with rotenone for a period of 14 days via oesophageal intubation, resulting in the successful establishment of a complex I deficient animal model. Upon optimisation of the rotenone concentration, rat diets were supplemented with high concentrations of either coenzyme Q10 or succinate for two days in an attempt to alleviate the biochemical manifestations of the rotenone induced complex I deficiency. Five tissue types were collected and assayed for a total of seven biochemical parameters, which enabled the establishment of a biochemical profile of response for each of the tissue groups. Data generated from the study revealed that rotenone, when dosed in high concentrations, contributed to the alleviation of serum hydro peroxide levels. This result was confirmed by the unexpected finding that rotenone itself harboured an antioxidant capacity equivalent to that of Trolox, the vitamin E analogue generally used for the determination of antioxidant capacity. It was therefore concluded that rotenone was not an ideal inhibitor for the evaluation of complex I deficiency and ROS-related investigations in an animal model. Since this compound is the most widely used inhibitor of complex I, the data from the study affirms the use of alternative complex l inhibition strategies. Finally, the data was suggestive of the fact that both coenzyme Q10 and succinate exclusively improved isolated components of the biochemical profile. Results generated in this study thus support current therapeutic intervention where patients receive a combination of vitamins and cofactors as part of a management strategy for the mitochondrial cytopathies.