Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy
Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy
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DOI：
10.1016/j.neulet.2010.05.025
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发表时间：
2010-07-19
影响因子：
2.5
通讯作者：
Englander, Ella W.
中科院分区：
文献类型：
--
作者：
Deng, Xiaoling;Vidal, Ruben;Englander, Ella W.
组织铁含量受到严格调控，以同时满足专门的代谢要求并避免毒性。铁蛋白是一种多亚基的铁储存蛋白，是维持脑内铁稳态的核心。铁蛋白轻链（FTL）编码基因的突变是常染色体显性遗传性神经退行性疾病神经铁蛋白病/遗传性铁蛋白病（HF）的基础。HF的特征在于铁蛋白和铁的进行性积累。为了深入了解FTL突变促进神经退行性变的机制，最近产生了表达人FTL突变形式的转基因小鼠。FTL小鼠表现出铁在大脑中的积累，并呈现出令人想起人类疾病的氧化应激表现。在这里，我们询问氧化DNA损伤是否在FTL小鼠大脑中积累。长距离PCR（L-PCR）扩增介导的DNA损伤检测分析显示，在12个月大的FTL小鼠中，脑中线粒体DNA（mtDNA）的完整性受到了显着损害，而不是6个月大的FTL小鼠。此外，L-PCR与DNA修饰酶结合使用，其靶向特定的DNA加合物，揭示了在FTL脑中mtDNA中积累的氧化加合物的类型。与预测在过度氧化应激条件下形成的DNA损伤一致，检测到的加合物包括氧化鸟嘌呤、脱碱基位点和链断裂。线粒体DNA损伤升高可能损害线粒体功能和脑能量学，并在长期内导致神经元丢失和加重HF中的神经变性。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Tissue iron content is strictly regulated to concomitantly satisfy specialized metabolic requirements and avoid toxicity. Ferritin, a multi-subunit iron storage protein, is central to maintenance of iron homeostasis in the brain. Mutations in the ferritin light chain (FTL)-encoding gene underlie the autosomal dominant, neurodegenerative disease, neuroferritinopathy/hereditary ferritinopathy (HF). HF is characterized by progressive accumulation of ferritin and iron. To gain insight into mechanisms by which FTL mutations promote neurodegeneration, a transgenic mouse, expressing human mutant form of FTL, was recently generated. The FTL mouse exhibits buildup of iron in the brain and presents manifestations of oxidative stress reminiscent of the human disease. Here, we asked whether oxidative DNA damage accumulates in the FTL mouse brain. Long-range PCR (L-PCR) amplification-mediated DNA damage detection assays revealed that the integrity of mitochondrial DNA (mtDNA) in the brain was significantly compromised in the 12- but not 6-month-old FTL mice. Furthermore, L-PCR employed in conjunction with DNA modifying enzymes, which target specific DNA adducts, revealed the types of oxidative adducts accumulating in mtDNA in the FTL brain. Consistently with DNA damage predicted to form under conditions of excessive oxidative stress, detected adducts include, oxidized guanines, abasic sites and strand breaks. Elevated mtDNA damage may impair mitochondrial function and brain energetics and in the long term contribute to neuronal loss and exacerbate neurodegeneration in HF. (C) 2010 Elsevier Ireland Ltd. All rights reserved.