Fukui Hirokazu, Moraes Carlos T
Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Hum Mol Genet. 2007 Apr 1;16(7):783-97. doi: 10.1093/hmg/ddm023. Epub 2007 Mar 13.
Mitochondrial abnormalities represent a major cytopathology in Huntington's disease (HD), a fatal neurodegenerative disease caused by CAG repeat expansions in the gene encoding huntingtin (Htt). In the present study, we investigated whether defects in the mitochondrial respiratory function are consequences of the expression of mutant Htt or they promote the formation of Htt aggregates. To take advantage of existing mitochondrial DNA mutants, we developed human osteosarcoma 143B cells expressing mutant Htt in an inducible manner and found that cells expressing mutant Htt but not wild-type Htt exhibited a reduced activity of complex III and an increased activity of complex IV. Conversely, pharmacological treatments that inhibited complex III activity significantly promoted the formation of Htt aggregates. This complex III-mediated modulation of Htt aggregates was also observed in a neuronal progenitor RN33B cell line transduced by lentivirus carrying mutant Htt. This effect of complex III inhibition on the Htt aggregates appeared to be mediated by the inhibition of proteasome activity, but not by ATP depletion or production of reactive oxygen species. Accordingly, complex III mutant cells also showed decreased proteasome activity. These results suggest the presence of a feedback system connecting the mitochondrial respiratory complex III and the production of Htt aggregates. Our results suggest that therapeutic interventions targeting complex III and/or proteasome could ameliorate the progress of HD.
线粒体异常是亨廷顿舞蹈症（HD）的主要细胞病理学特征，HD是一种由编码亨廷顿蛋白（Htt）的基因中CAG重复序列扩增引起的致命神经退行性疾病。在本研究中，我们调查了线粒体呼吸功能缺陷是突变型Htt表达的结果，还是它们促进了Htt聚集体的形成。为了利用现有的线粒体DNA突变体，我们构建了以可诱导方式表达突变型Htt的人骨肉瘤143B细胞，发现表达突变型Htt而非野生型Htt的细胞表现出复合物III活性降低和复合物IV活性增加。相反，抑制复合物III活性的药物治疗显著促进了Htt聚集体的形成。在携带突变型Htt的慢病毒转导的神经元祖细胞系RN33B中也观察到了这种复合物III介导的Htt聚集体调节作用。复合物III抑制对Htt聚集体的这种作用似乎是由蛋白酶体活性的抑制介导的，而不是由ATP耗竭或活性氧的产生介导的。因此，复合物III突变细胞也显示出蛋白酶体活性降低。这些结果表明存在一个连接线粒体呼吸复合物III和Htt聚集体产生的反馈系统。我们的结果表明，针对复合物III和/或蛋白酶体的治疗干预可能会改善HD的进展。
