Increase in mitochondrial DNA mutations impairs retinal function and renders the retina vulnerable to injury
Increase in mitochondrial DNA mutations impairs retinal function and renders the retina vulnerable to injury
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DOI：
10.1111/j.1474-9726.2011.00690.x
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发表时间：
2011-08-01
期刊：
影响因子：
7.8
通讯作者：
Crowston, Jonathan G.
中科院分区：
文献类型：
--
作者：
Kong, Yu X. G.;Van Bergen, Nicole;Crowston, Jonathan G.
由于线粒体聚合酶γ(Polg)校对功能受损而积累高水平线粒体DNA(MtDNA)突变的小鼠模型已被证明发展出与加速衰老一致的表型。由于mtDNA突变增加和衰老是神经退行性疾病的风险因素，我们试图确定mtDNA突变增加是否会使神经元更容易受到损伤。因此，我们在转基因小鼠中检测了视网膜神经元的体内功能活动及其应对压力的能力，转基因小鼠携带神经靶向突变Polg基因，但校对能力受损(Kasahara等人)。(2006)摩尔精神病学11(6)：577-93,523)。我们证实，这些转基因小鼠的视网膜增加了线粒体DNA的缺失和点突变，并减少了线粒体氧化磷酸化酶的表达。与这些变化相关的是，通过暗适应视网膜电信号测量，Polg转基因小鼠表现出与年龄相关的视网膜功能加速丧失，特别是在视网膜内侧和中部。此外，在Polg转基因小鼠中，视网膜神经节细胞主导的视网膜内功能显示出更容易受到眼压升高引起的损伤，眼压升高是一种已知的在视网膜产生机械、代谢和氧化应激的侮辱。这些发现表明，mtDNA突变的积累与体内神经功能受损和神经元抵抗外部应激的能力降低有关，这表明衰老的中枢神经系统更容易发生神经退化。
Mouse models that accumulate high levels of mitochondrial DNA (mtDNA) mutations owing to impairments in mitochondrial polymerase gamma (PolG) proofreading function have been shown to develop phenotypes consistent with accelerated aging. As increase in mtDNA mutations and aging are risk factors for neurodegenerative diseases, we sought to determine whether increase in mtDNA mutations renders neurons more vulnerable to injury. We therefore examined the in vivo functional activity of retinal neurons and their ability to cope with stress in transgenic mice harboring a neural-targeted mutant PolG gene with an impaired proofreading capability (Kasahara, et al. (2006) Mol Psychiatry 11(6):577-93, 523). We confirmed that the retina of these transgenic mice have increased mtDNA deletions and point mutations and decreased expression of mitochondrial oxidative phosphorylation enzymes. Associated with these changes, the PolG transgenic mice demonstrated accelerated age-related loss in retinal function as measured by dark-adapted electroretinogram, particularly in the inner and middle retina. Furthermore, the retinal ganglion cell-dominant inner retinal function in PolG transgenic mice showed greater vulnerability to injury induced by raised intraocular pressure, an insult known to produce mechanical, metabolic, and oxidative stress in the retina. These findings indicate that an accumulation of mtDNA mutations is associated with impairment in neural function and reduced capacity of neurons to resist external stress in vivo, suggesting a potential mechanism whereby aging central nervous system can become more vulnerable to neurodegeneration.