Analysis of gene expression profiles from the liver of rats treated with the mitochondrial electron transport chain complex III inhibitor GSK932121A (50mg/kg) or vehicle control

BACKGROUND: Correlating in vitro mitochondrial data to outcomes in vivo remains a challenge and improving methods to assess mitochondrial function in vivo would both guide safer candidate selection and support the growing number of discovery programmes targeting mitochondria for pharmacological intervention. OBJECTIVES: The aim was to assess the toxicity profile of a compound with complex III electron transport chain inhibitory activity (GSK932121A) in order to identify markers and mechanisms of mitochondrial perturbation in vivo. METHODS:Crl:CD(SD) rats were dosed IP with GSK932121A for up to 5 hours depending upon the severity of observed clinical signs. Respirometry, microscopy, lactate/pyruvate and transcriptomics profiling were used to aid identification of a mode of action and this data was compared with functional data in isolated mitochondria. RESULTS AND DISCUSSION: GSK932121A administered in vivo caused hypothermia and a metabolic shift in energy production provoking an increased lactate/pyruvate ratio, microvesicular steatosis and glycogen depletion; alongside gene expression changes indicative of a fasted state. Our data improves current understanding of the toxicological consequences of drug induced respiratory chain inhibition and guides endpoint selection for future investigative safety studies with mitochondrially active molecules.