Mitochondrial transcription factor A overexpression and base excision repair deficiency in the inner ear of rats with d‐galactose‐induced aging
Mitochondrial transcription factor A overexpression and base excision repair deficiency in the inner ear of rats with d‐galactose‐induced aging
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DOI：
10.1111/j.1742-4658.2011.08176.x
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发表时间：
2011-07
期刊：
影响因子：
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通讯作者：
Yi Zhong;Yu-juan Hu;Bei Chen;W. Peng;Yu Sun;Yang Yang-Yang;Xueyang Zhao;G. Fan;Xiang Huang-
中科院分区：
文献类型：
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作者：
Yi Zhong;Yu-juan Hu;Bei Chen;W. Peng;Yu Sun;Yang Yang-Yang;Xueyang Zhao;G. Fan;Xiang Huang-
线粒体DNA的氧化损伤与过量的活性氧产生有关。线粒体常见缺失（人类和大鼠mtDNA 4977 bp和4834 bp缺失）是与衰老和退行性疾病相关的mtDNA损伤的最典型和最常见形式。线粒体常见缺失的积累被认为在年龄相关性听力损失（老年性耳聋）中起着至关重要的作用。然而，线粒体DNA缺失的形成和积累的机制仍然不清楚。在本研究中，使用d-Gal诱导的大鼠模拟衰老模型来探索缺失突变的起源以及mtDNA修复系统如何在衰老过程中调节内耳的这一过程。我们发现，与对照组相比，d-Gal处理大鼠内耳中线粒体常见缺失大大增加，线粒体碱基切除修复能力显著降低。d-Gal诱导的线粒体转录因子A的过表达显著刺激mtDNA复制，导致mtDNA拷贝数增加。此外，在d-Gal处理的大鼠中观察到内耳听觉感觉细胞的年龄相关损失。两者合计，我们的数据表明，线粒体碱基切除修复能力不足和线粒体转录因子A过度表达导致的mtDNA复制增加可能有助于在衰老过程中内耳mtDNA缺失的积累。这项研究也为老年性耳聋的发展提供了新的见解。
Oxidative damage to mtDNA is associated with excessive reactive oxygen species production. The mitochondrial common deletion (mtDNA 4977‐bp and 4834‐bp deletion in humans and rats, respectively) is the most typical and frequent form of mtDNA damage associated with aging and degenerative diseases. The accumulation of the mitochondrial common deletion has been proposed to play a crucial role in age‐related hearing loss (presbycusis). However, the mechanisms underlying the formation and accumulation of mtDNA deletions are still obscure. In the present study, a rat mimetic aging model induced by d‐Gal was used to explore the origin of deletion mutations and how mtDNA repair systems modulate this process in the inner ear during aging. We found that the mitochondrial common deletion was greatly increased and mitochondrial base excision repair capacity was significantly reduced in the inner ear in d‐Gal‐treated rats as compared with controls. The overexpression of mitochondrial transcription factor A induced by d‐Gal significantly stimulated mtDNA replication, resulting in an increase in mtDNA copy number. In addition, an age‐related loss of auditory sensory cells in the inner ear was observed in d‐Gal‐treated rats. Taken together, our data suggest that mitochondrial base excision repair capacity deficiency and an increase in mtDNA replication resulting from mitochondrial transcription factor A overexpression may contribute to the accumulation of mtDNA deletions in the inner ear during aging. This study also provides new insights into the development of presbycusis.