Fernández Ana, Martínez-Ramírez Carmen, Gómez Ana, de Diego Antonio M G, Gandía Luis, Casarejos María José, García Antonio G
Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Fundación Teófilo Hernando, Parque científico de Madrid, Cantoblanco, Madrid, Spain.
Servicio de Neurobiología, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Neurobiol Dis. 2023 Apr;179:106046. doi: 10.1016/j.nbd.2023.106046. Epub 2023 Feb 18.
From a pathogenic perspective, Huntington's disease (HD) is being considered as a synaptopathy. As such, alterations 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 peripheral 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 (I). 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 I inhibition by FCCP; and (vii) lesser potentiation by BayK8644 of I and smaller prolongation of current deactivation. 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 mitochondrial 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 peripheral tissues.
从致病角度来看，亨廷顿舞蹈症（HD）被视为一种突触病。因此，大脑神经递质释放会发生改变。由于交感肾上腺轴的活动受中枢控制，儿茶酚胺释放的胞吐作用也可能出现缺陷。事实上，在HD的R6/1模型的肾上腺髓质嗜铬细胞（CCs）中，已报道分泌减少和胞吐融合孔动力学改变。这些改变可能与外周CCs中发生的线粒体缺陷有关，类似于在脑线粒体中所描述的情况。在此，我们探究了线粒体结构和功能的改变及其对胞吐作用和钙通道电流（I）的影响。我们监测了与这些事件相关的各种参数，在野生型（WT）和HD的R6/1小鼠模型的疾病前期（2月龄，2m）以及出现运动缺陷时（7月龄，7m）进行监测。在来自7m的分离CCs以及R6/1小鼠的肾上腺髓质中，我们发现了以下改变（相对于7m的WT小鼠）：（i）线粒体碎片化增加以及氧化应激增强，氧化型谷胱甘肽增加；（ii）基础呼吸和最大呼吸减少；（iii）细胞内ATP水平降低；（iv）线粒体去极化；（v）儿茶酚胺释放急剧减少，质子载体FCCP的增强作用较差；（vi）FCCP对I的抑制作用降低；（vii）BayK8644对I的增强作用较小，电流失活的延长也较小。值得注意的是，其中一些改变在疾病前期的2m R6/1小鼠的CCs中就已出现。基于这些结果，可以提出一个合理的假设，即线粒体功能改变似乎是HD发病机制中的早期主要事件。这与最近在各种HD外周组织中报道的越来越多的线粒体、代谢和炎症改变是一致的。
