Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11835-40. doi: 10.1073/pnas.0914569107. Epub 2010 Jun 14.
Mitochondrial genomes with deleterious mutations can replicate in cells along with wild-type genomes in a state of heteroplasmy, and are a cause of severe inherited syndromes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), and Leber's hereditary optic neuropathy (LHON). The cytosolic E3 ligase, Parkin, commonly mutated in recessive familial parkinsonism, translocates to depolarized mitochondria and induces their autophagic elimination, suggesting that Parkin may signal the selective removal of defective mitochondria within the cell. We report that long-term overexpression of Parkin can eliminate mitochondria with deleterious COXI mutations in heteroplasmic cybrid cells, thereby enriching cells for wild-type mtDNA and restoring cytochrome c oxidase activity. After relieving cybrid cells of Parkin overexpression, a more favorable wild-type to mutant mitochondrial genome ratio is stably maintained. These data support the model that Parkin functions in a mitochondrial quality control pathway. Additionally, they suggest that transiently increasing levels of Parkin expression might ameliorate certain mitochondrial diseases.
携带有害突变的线粒体基因组可以与野生型基因组在异质状态下在细胞中复制，是严重遗传综合征的原因，如线粒体肌病、脑病、乳酸酸中毒和中风（MELAS）、神经病、共济失调、视网膜色素变性-母系遗传 Leigh 综合征（NARP-MILS）和 Leber 遗传性视神经病变（LHON）。细胞质 E3 连接酶 Parkin，通常在隐性家族性帕金森病中发生突变，易位到去极化的线粒体并诱导其自噬消除，表明 Parkin 可能信号选择性去除细胞内有缺陷的线粒体。我们报告说，Parkin 的长期过表达可以消除异质杂交细胞中具有有害 COXI 突变的线粒体，从而使细胞富含野生型 mtDNA 并恢复细胞色素 c 氧化酶活性。在解除 Parkin 过表达的杂交细胞后，更有利的野生型到突变线粒体基因组比例可以稳定维持。这些数据支持 Parkin 在线粒体质量控制途径中发挥作用的模型。此外，它们表明暂时增加 Parkin 表达水平可能改善某些线粒体疾病。
