Mitochondrial dysfunction in chromaffin cells from the R6/1 mouse model of Huntington?s disease: Impact on exocytosis and calcium current regulation

From a pathogenic perspective, Huntington's disease (HD) is being considered as a synaptopathy. As such, al-terations in brain neurotransmitter release occur. As the activity of the sympathoadrenal axis is centrally controlled, deficits in the exocytotic release of catecholamine release may also occur. In fact, in chromaffin cells (CCs) of the adrenal medulla of the R6/1 model of HD, decrease of secretion and altered kinetics of the exocytotic fusion pore have been reported. Those alterations could be linked to mitochondrial deficits occurring in pe-ripheral CCs, similar to those described in brain mitochondria. Here we have inquired about alterations in mitochondrial structure and function and their impact on exocytosis and calcium channel currents (ICa). We have monitored various parameters linked to those events, in wild type (WT) and the R6/1 mouse model of HD at a pre-disease stage (2 months age, 2 m), and when motor deficits are present (7 months age, 7 m). In isolated CCs from 7 m and in the adrenal medulla of R6/1 mice, we found the following alterations (with respect 7 m WT mice): (i) augmented fragmented mitochondria and oxidative stress with increased oxidized glutathione; (ii) decreased basal and maximal respiration; (iii) diminution of ATP cell levels; (iv) mitochondrial depolarization; (v) drastic decrease of catecholamine release with poorer potentiation by protonophore FCCP; (vi) decreased ICa inhibition by FCCP; and (vii) lesser potentiation by BayK8644 of ICa and smaller prolongation of current deac-tivation. Of note was the fact several of these alterations were already manifested in CCs from 2 m R6/1 mice at pre-disease stages. Based on those results, a plausible hypothesis can be raised in the sense that altered mito-chondrial function seems to be an early primary event in HD pathogenesis. This is in line with an increasing number of mitochondrial, metabolic, and inflammatory alterations being recently reported in various HD pe-ripheral tissues.

Automated summary

From a pathogenic perspective, Huntington's disease (HD) is considered a synaptopathy with alterations in neurotransmitter release and catecholamine secretion in chromaffin cells (CCs). This study explored the impact of mitochondrial deficits on CCs in a mouse model of HD. The results showed fragmented mitochondria, oxidative stress, decreased respiration and ATP levels, mitochondrial depolarization, and impaired catecholamine release and calcium channel currents. These alterations were observed at an early disease stage, suggesting that mitochondrial dysfunction is a primary event in HD pathogenesis.