Mitochondrial DNA Damage Level Determines Neural Stem Cell Differentiation Fate
Mitochondrial DNA Damage Level Determines Neural Stem Cell Differentiation Fate
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DOI：
10.1523/jneurosci.0852-11.2011
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发表时间：
2011-06-29
影响因子：
5.3
通讯作者：
Eide, Lars
中科院分区：
文献类型：
--
作者：
Wang, Wei;Esbensen, Ying;Eide, Lars
神经干细胞（NSCs）的线粒体DNA （mtDNA）容易受到氧化损伤。除了调节NSC分化谱系外，对细胞氧化还原状态的微妙操纵还会影响mtDNA的完整性，这表明mtDNA完整性与分化调节之间存在分子联系。在线粒体氧化应激过程中，8-氧鸟嘌呤DNA糖基化酶（OGG1）对修复线粒体DNA损伤和NSC活力至关重要。从ogg1（-/-）敲除小鼠中分化的神经细胞自发地积累mtDNA损伤，并随之将其分化方向转向星形细胞谱系，类似于遭受mtDNA损伤损伤的wt NSCs。抗氧化处理逆转了mtDNA损伤积累，并单独增加了ogg1（-/-）细胞的神经发生。来自表达线粒体靶向人ogg1的转基因ogg1（-/-）小鼠的NSCs在分化过程中免受mtDNA损伤，并表现出神经发生的升高。这种分化方向转变的潜在机制涉及通过增加ogg1（-/-）细胞中NAD/NADH比率来促进Sirt1的星形发生。氧化还原操作改变mtDNA损伤水平，相应地激活了两种细胞类型中的Sirt1。我们的研究结果首次证明了mtDNA完整性与NSC分化命运之间的相互依存关系，表明mtDNA损伤是神经元损伤修复过程中星形胶质细胞增生和神经发生缺乏的主要信号。
The mitochondrial DNA (mtDNA) of neural stem cells (NSCs) is vulnerable to oxidation damage. Subtle manipulations of the cellular redox state affect mtDNA integrity in addition to regulating the NSC differentiation lineage, suggesting a molecular link between mtDNA integrity and regulation of differentiation. Here we show that 8-oxoguanine DNA glycosylase (OGG1) is essential for repair of mtDNA damage and NSC viability during mitochondrial oxidative stress. Differentiating neural cells from ogg1(-/-) knock-out mice spontaneously accumulate mtDNA damage and concomitantly shift their differentiation direction toward an astrocytic lineage, similar to wt NSCs subjected to mtDNA damaging insults. Antioxidant treatments reversed mtDNA damage accumulation and separately increased neurogenesis in ogg1(-/-) cells. NSCs from a transgenic ogg1(-/-) mouse expressing mitochondrially targeted human OGG1 were protected from mtDNA damage during differentiation, and displayed elevated neurogenesis. The underlying mechanisms for this shift in differentiation direction involve the astrogenesis promoting Sirt1 via an increased NAD/NADH ratio in ogg1(-/-) cells. Redox manipulations to alter mtDNA damage level correspondingly activated Sirt1 in both cell types. Our results demonstrate for the first time the interdependence between mtDNA integrity and NSC differentiation fate, suggesting that mtDNA damage is the primary signal for the elevated astrogliosis and lack of neurogenesis seen during repair of neuronal injury.