Tan Wenzhi, Pasinelli Piera, Trotti Davide
Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for the Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for the Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Biochim Biophys Acta. 2014 Aug;1842(8):1295-301. doi: 10.1016/j.bbadis.2014.02.009. Epub 2014 Feb 22.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an adult onset characterized by loss of both upper and lower motor neurons. In ~10% of cases, patients developed ALS with an apparent genetic linkage (familial ALS or fALS). Approximately 20% of fALS displays mutations in the SOD1 gene encoding superoxide dismutase 1. There are many proposed cellular and molecular mechanisms among which, mitochondrial dysfunctions occur early, prior to symptoms occurrence. In this review, we modeled the effect of mutant SOD1 protein via the formation of a toxic complex with Bcl2 on mitochondrial bioenergetics. Furthermore, we discuss that the shutdown of ATP permeation through mitochondrial outer membrane could lead to both respiration inhibition and temporary mitochondrial hyperpolarization. Moreover, we reviewed mitochondrial calcium signaling, oxidative stress, fission and fusion, autophagy and apoptosis in mutant SOD1-linked ALS. Functional defects in mitochondria appear early before symptoms are manifested in ALS. Therefore, mitochondrial dysfunction is a promising therapeutic target in ALS.
肌萎缩侧索硬化症（ALS）是一种成年发病的致命性神经退行性疾病，其特征是上下运动神经元均丧失。在约10%的病例中，患者患的是具有明显遗传连锁性的ALS（家族性ALS或fALS）。大约20%的fALS患者在编码超氧化物歧化酶1的SOD1基因中存在突变。目前提出了许多细胞和分子机制，其中线粒体功能障碍在症状出现之前就早早发生了。在本综述中，我们通过突变型SOD1蛋白与Bcl2形成毒性复合物来模拟其对线粒体生物能量学的影响。此外，我们讨论了通过线粒体外膜的ATP渗透关闭可能导致呼吸抑制和线粒体暂时超极化。此外，我们还综述了与突变型SOD1相关的ALS中的线粒体钙信号传导、氧化应激、裂变和融合、自噬和凋亡。线粒体功能缺陷在ALS症状出现之前就早早出现了。因此，线粒体功能障碍是ALS中一个很有前景的治疗靶点。
