6-Hydroxydopamine induces different mitochondrial bioenergetics response in brain regions of rat

Abstract

Mitochondrial dysfunction has been demonstrated to have a central role in Parkinson Disease (PD) pathophysiology. Some studies have indicated that PD causes an impairment in mitochondrial bioenergetics; however, the effects of PD on brain-region specific bioenergetics was never investigated before. This study aimed to evaluate mitochondrial bioenergetics in different rat brain structures in an in vitro model of PD using 6-OHDA. Rat brain slices of hippocampus, striatum, and cortex were exposed to 6-OHDA (100 μM) for 1 h and mitochondrial bioenergetic parameters, peroxide production, lactate dehydrogenase (LDH) and citrate synthase (CS) activities were analyzed. Hippocampus slices exposed to 6-OHDA presented increased peroxide production but, no mitochondrial adaptive response against 6-OHDA damage. Cortex slices exposed to 6-OHDA presented increased oxygen flux related to oxidative phosphorylation and energetic pathways exchange demonstrated by the increase in LDH activity, suggesting a mitochondrial compensatory response. Striatum slices exposed to 6-OHDA presented a decrease of oxidative phosphorylation and decrease of oxygen flux related to ATP-synthase indicating an impairment in the respiratory chain. The co-incubation of 6-OHDA with n-acetylcysteine (NAC) abolished the effects of 6-OHDA on mitochondrial function in all brain regions tested, indicating that the increased reactive oxygen species (ROS) production is responsible for the alterations observed in mitochondrial bioenergetics. The present results indicate a brain-region specific response against 6-OHDA, providing new insights into brain mitochondrial bioenergetic function in PD. These findings may contribute to the development of future therapies with a target on energy metabolism.

Keywords: High-resolution respirometry; Mitochondrial function; Neurodegenerative disease; Parkinson disease; ROS production.