Pleiotropic role of melatonin in brain mitochondria of obese mice

Abstract

Obesity induced by a leptin deficiency causes extensive damage in brain due to a large increase in oxidative stress. Mitochondria have a central role in this neural damage. Leptin receptors have a wide expression in the brain and its absence is associated with reduced mitochondrial respiration by a decoupled electron transport chain and a significantly increased complex II activity which is major player in mitochondrial free radical generation. The consequences are an abrupt reduction in ATP production and a reduced activity of the tricarboxylic acid (TCA) cycle, evidence of dysfunction of processes related to energy production, the reduction of which contributes to multiple brain pathologies. Melatonin, a major protector of mitochondria against free radicals with a significant influence on glucose metabolism, has been shown to counteract these conditions. In the present study the main respirasome expression was recovered by melatonin, with a reduction in complex II activity and the complex II dependent free radical generation. Additionally, melatonin normalized the TCA cycle. Reduction in ATP synthesis was caused by UCP2 activation. The uninterrupted sensation of starvation due to leptin deficiency involves impairments in glucose metabolism, which was reversed by melatonin via negatively acting on hexokinase II, a key regulator of glycolysis and major contributor to the Warburg effect. Hexokinase II reduction was accompanied by a significant Bcl-2 reduction, inducing a delicate readjustment of pro and anti-apoptotic proteins in the mitochondria to preserve cell survival, which was associated with a marked reduction of the Bax activator, Puma, observed in obese animals treated by melatonin.