Keeney Paula M, Dunham Lisa D, Quigley Caitlin K, Morton Stephanie L, Bergquist Kristen E, Bennett James P
Morris K. Udall Parkinson's Research Center of Excellence, University of Virginia, PO Box 800394, Charlottesville, VA 22908, USA.
Exp Neurol. 2009 Dec;220(2):374-82. doi: 10.1016/j.expneurol.2009.09.025. Epub 2009 Oct 6.
Sporadic Parkinson's disease (sPD) is a nervous system-wide disease that presents with a bradykinetic movement disorder and frequently progresses to include depression and cognitive impairment. Cybrid models of sPD are based on expression of sPD platelet mitochondrial DNA (mtDNA) in neural cells and demonstrate some similarities to sPD brains. In sPD and CTL cybrids we characterized aspects of mitochondrial biogenesis, mtDNA genomics, composition of the respirasome and the relationships among isolated mitochondrial and intact cell respiration. Cybrid mtDNA levels varied and correlated with expression of PGC-1 alpha, a transcriptional co-activator regulator of mitochondrial biogenesis. Levels of mtDNA heteroplasmic mutations were asymmetrically distributed across the mitochondrial genome; numbers of heteroplasmies were more evenly distributed. Neither levels nor numbers of heteroplasmies distinguished sPD from CTL. sPD cybrid mitochondrial ETC subunit protein levels were not altered. Isolated mitochondrial complex I respiration rates showed limited correlation with whole cell complex I respiration rates in both sPD and CTL cybrids. Intact cell respiration during the normoxic-anoxic transition yielded K(m) values for oxygen that directly related to respiration rates in CTL but not in sPD cell lines. Both sPD and CTL cybrid cells are substantially heterogeneous in mitochondrial genomic and physiologic properties. Our results suggest that mtDNA depletion may occur in sPD neurons and could reflect impairment of mitochondrial biogenesis. Cybrids remain a valuable model for some aspects of sPD but their heterogeneity mitigates against a simple designation of sPD phenotype in this cell model.
散发性帕金森病（sPD）是一种累及全神经系统的疾病，表现为运动迟缓性运动障碍，且常进展为包括抑郁和认知障碍在内的症状。sPD的细胞杂交模型基于sPD血小板线粒体DNA（mtDNA）在神经细胞中的表达构建，并且与sPD大脑表现出一些相似性。在sPD和对照细胞杂交体中，我们对线粒体生物发生、mtDNA基因组学、呼吸体组成以及分离的线粒体呼吸与完整细胞呼吸之间的关系进行了表征。细胞杂交体的mtDNA水平各不相同，且与线粒体生物发生的转录共激活调节因子PGC-1α的表达相关。mtDNA异质性突变水平在线粒体基因组中呈不对称分布；异质性数量分布更为均匀。异质性的水平和数量均无法区分sPD和对照。sPD细胞杂交体线粒体电子传递链（ETC）亚基蛋白水平未发生改变。在sPD和对照细胞杂交体中，分离的线粒体复合体I呼吸速率与全细胞复合体I呼吸速率的相关性均有限。常氧-缺氧转变期间的完整细胞呼吸产生的氧的米氏常数（K(m)）值与对照细胞中的呼吸速率直接相关，但与sPD细胞系中的呼吸速率无关。sPD和对照细胞杂交体在 mitochondrial genomic and physiologic properties方面均存在显著异质性。我们的结果表明，sPD神经元中可能发生mtDNA耗竭，这可能反映了线粒体生物发生的受损。细胞杂交体在sPD的某些方面仍然是一个有价值的模型，但其异质性不利于在该细胞模型中简单地确定sPD表型。 （最后一句原文可能有误，推测正确表述后翻译，原句中“mitochondrial genomic and physiologic properties”表述不太准确，推测应该是“线粒体基因组和生理特性”之类含义）
