Gegg Matthew E, Cooper J Mark, Schapira Anthony H V, Taanman Jan-Willem
Department of Clinical Neurosciences, Institute of Neurology, University College London, Queen Square, London, United Kingdom.
PLoS One. 2009;4(3):e4756. doi: 10.1371/journal.pone.0004756. Epub 2009 Mar 9.
Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Impairment of the mitochondrial electron transport chain (ETC) and an increased frequency in deletions of mitochondrial DNA (mtDNA), which encodes some of the subunits of the ETC, have been reported in the substantia nigra of PD brains. The identification of mutations in the PINK1 gene, which cause an autosomal recessive form of PD, has supported mitochondrial involvement in PD. The PINK1 protein is a serine/threonine kinase localized in mitochondria and the cytosol. Its precise function is unknown, but it is involved in neuroprotection against a variety of stress signalling pathways.
METHODOLOGY/PRINCIPAL FINDINGS: In this report we have investigated the effect of silencing PINK1 expression in human dopaminergic SH-SY5Y cells by siRNA on mtDNA synthesis and ETC function. Loss of PINK1 expression resulted in a decrease in mtDNA levels and mtDNA synthesis. We also report a concomitant loss of mitochondrial membrane potential and decreased mitochondrial ATP synthesis, with the activity of complex IV of the ETC most affected. This mitochondrial dysfunction resulted in increased markers of oxidative stress under basal conditions and increased cell death following treatment with the free radical generator paraquat.
This report highlights a novel function of PINK1 in mitochondrial biogenesis and a role in maintaining mitochondrial ETC activity. Dysfunction of both has been implicated in sporadic forms of PD suggesting that these may be key pathways in the development of the disease.
线粒体功能障碍与帕金森病（PD）的发病机制有关。据报道，在PD患者大脑的黑质中，线粒体电子传递链（ETC）受损，且编码ETC某些亚基的线粒体DNA（mtDNA）缺失频率增加。PINK1基因突变导致常染色体隐性遗传型PD，这一发现支持了线粒体与PD发病有关的观点。PINK1蛋白是一种丝氨酸/苏氨酸激酶，定位于线粒体和细胞质中。其确切功能尚不清楚，但它参与了针对多种应激信号通路的神经保护作用。
方法/主要发现：在本报告中，我们研究了通过小干扰RNA（siRNA）沉默人多巴胺能SH-SY5Y细胞中PINK1表达对mtDNA合成和ETC功能的影响。PINK1表达缺失导致mtDNA水平和mtDNA合成减少。我们还报告了线粒体膜电位随之丧失以及线粒体ATP合成减少，其中ETC复合体IV的活性受影响最大。这种线粒体功能障碍导致基础条件下氧化应激标志物增加，在用自由基生成剂百草枯处理后细胞死亡增加。
本报告突出了PINK1在 mitochondrial biogenesis中的新功能以及在维持线粒体ETC活性中的作用。两者功能障碍都与散发性PD有关，提示这些可能是该疾病发展的关键途径。 （注：“mitochondrial biogenesis”可能是“线粒体生物合成”的错误拼写，这里按正确理解翻译为“线粒体生物合成”）
