线粒体功能异常与亨廷顿舞蹈病的病理发生机制

Role of Mitochondrial Dysfunction in Huntington's Disease

亨廷顿舞蹈病(Huntington’s disease,HD)是一种致命的遗传性神经退行性疾病,它是由亨廷顿蛋白N-端的多聚谷氨酰胺延长造成的。该病表现为纹状体中的中型棘神经元(medium spiny neurons,MSN)逐渐丢失。HD的致病机理还不完全清楚,目前越来越多的研究结果显示线粒体在HD中发挥着重要作用。已有证据充分表明了HD细胞中线粒体的形态和结构发生了明显改变。此外,HD细胞中线粒体某些电子传递链复合物蛋白活性或蛋白表达水平的降低,以及突变亨廷顿蛋白对细胞核基因转录的影响进一步引起了线粒体功能障碍。除了线粒体形态和功能的改变,HD细胞线粒体的Ca2+稳态也发生了紊乱,且线粒体的氧化压力水平显著升高,进而导致HD细胞线粒体基因组DNA损伤。由于线粒体在细胞凋亡过程发挥着重要作用,因此HD细胞中线粒体的这些变化揭示了线粒体异常参与了HD细胞特别是HD神经细胞的凋亡过程。本综述将集中探讨HD中线粒体的一系列异常变化,为阐明HD的发病机理和HD治疗提供一些启发。

Huntington’s disease （HD） is a fatal inherited neurodegenerative disorder with the progressive loss of striatal medium spiny neurons （MSN）, caused by a polyglutamine expansion in the N-terminus of huntingtin protein. Pathogenic mechanism of HD is not fully understood, but increasing evidences indicate that dysfunction of mitochondria plays an important role in HD pathogenesis. The morphology and structure of mitochondria in HD are changed due to a series of pathogenic factors. Moreover, the activity and/or expression levels of some mitochondrial electron transport chain protein complexes are decreased, and the mitochondrial biogenesis is impaired by mutant huntingtin protein. Furthermore, dysregulation of mitochondrial Ca2＋ homeostasis and excessive mitochondrial oxidant generation have been recently demonstrated in HD cells/neurons.All of these changes in HD mitochondria could cause the dysfunction of mitochondria, which in turn lead to cell death in HD cells, especially in neuron. This review will focus on the role of mitochondrial dysfunction in the pathogenesis of HD and the therapeutic strategy targeted on mitochondria for the treatment of HD.