Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma.
Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma.
复制标题
累积 mtDNA 损伤和突变导致青光眼大鼠模型中 RGC 逐渐丧失
DOI：
10.1016/j.nbd.2014.11.014
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发表时间：
2015-02
影响因子：
6.1
通讯作者：
Sun XH
中科院分区：
文献类型：
--
作者：
Wu JH;Zhang SH;Nickerson JM;Gao FJ;Sun Z;Chen XY;Zhang SJ;Gao F;Chen JY;Luo Y;Wang Y;Sun XH
青光眼是一种慢性神经退行性疾病，其特征是视网膜神经节细胞（RGC）的进行性丧失。线粒体DNA（mtDNA）的改变已被记录为许多神经退行性疾病的关键组成部分。但是，mtDNA的改变是否有助于RGC的进行性丧失以及这种现象可能发生的机制。我们使用慢性眼内高血压的大鼠模型研究了RGC中的mtDNA改变，并探索了渐进性RGC损失的机制。我们证明，由眼内压（IOP）升高引起的mtDNA损伤和突变是在级联反应中引发的关键事件，导致渐进的RGC损失。 MTDNA的损害和突变，线粒体功能障碍，MTDNA修复/复制酶的水平降低以及升高的活性氧形成了一个正反馈回路，从而产生不可逆的mtDNA损伤和突变，并在返回渐进的RGC丢失后，也会造成返回的渐进率。正常IOP。此外，我们证明mtDNA损伤和突变增加了RGC对IOP和谷氨酸升高的脆弱性，这是最常见的青光眼损伤之一。这项研究表明，针对MTDNA维持和维修并促进能源生产的治疗方法可能会阻止RGC的逐渐死亡。
Glaucoma is a chronic neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Mitochondrial DNA (mtDNA) alterations have been documented as a key component of many neurodegenerative disorders. However, whether mtDNA alterations contribute to the progressive loss of RGCs and the mechanism whereby this phenomenon could occur are poorly understood. We investigated mtDNA alterations in RGCs using a rat model of chronic intraocular hypertension and explored the mechanisms underlying progressive RGC loss. We demonstrate that the mtDNA damage and mutations triggered by intraocular pressure (IOP) elevation are initiating, crucial events in a cascade leading to progressive RGC loss. Damage to and mutation of mtDNA, mitochondrial dysfunction, reduced levels of mtDNA repair/replication enzymes, and elevated reactive oxygen species form a positive feedback loop that produces irreversible mtDNA damage and mutation and contributes to progressive RGC loss, which occurs even after a return to normal IOP. Furthermore, we demonstrate that mtDNA damage and mutations increase the vulnerability of RGCs to elevated IOP and glutamate levels, which are among the most common glaucoma insults. This study suggests that therapeutic approaches that target mtDNA maintenance and repair and that promote energy production may prevent the progressive death of RGCs.