Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase dependent mechanism
Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase dependent mechanism
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DOI：
10.1523/jneurosci.5654-07.2008
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发表时间：
2008-02-27
影响因子：
5.3
通讯作者：
Piantadosi, Claude A.
中科院分区：
文献类型：
--
作者：
Gutsaeva, Diana R.;Carraway, Martha Sue;Piantadosi, Claude A.
在低氧期间和之后保护大脑代谢的适应性机制，例如，在低氧预适应期间，部分地由一氧化氮(NO)协调。我们验证了以下假设：在野生型(Wt)和神经型一氧化氮合酶(NNOS)和内皮型一氧化氮合酶(ENOS)缺陷小鼠的皮层下，急性一过性低氧刺激一氧化氮合酶(NOS)激活的线粒体生物发生机制。将小鼠暴露于低压低氧6h，观察线粒体生物发生即刻低氧转录调控的变化与线粒体DNA含量和线粒体密度的关系。不同品系小鼠的脑血流量和海马区P0(2)对急性缺氧的反应没有差异。在Wt小鼠中，低氧使过氧化体增殖物激活受体-γ共激活物-1α(PGC-1α)、核呼吸因子-1和线粒体转录因子A的mRNA水平升高。24小时后，新的线粒体出现在表达线粒体绿色荧光蛋白的报告小鼠的海马神经元中。ENOS(-/-)小鼠表现出较低的基础水平，但保持对这些转录本的低氧诱导。相比之下，nNOS(-/-)小鼠线粒体生物发生的核转录调节在基线时是正常的，但对缺氧没有反应。低氧后，Wt和eNOS(-/-)小鼠皮质下mtDNA含量增加，而nNOS(-/-)小鼠无明显变化。低氧可刺激Wt小鼠PGC-1α蛋白表达及蛋白激酶A和cAMP反应元件结合蛋白的磷酸化，但CREB仅在eNOS(-/-)小鼠中被激活，而在nNOS(-/-)小鼠中不被激活。这些发现表明，低氧预适应通过一种新的机制诱导皮质下线粒体的生物发生，这种新机制需要nNOS对PGC-1α和CREB进行调节。
The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, during hypoxic preconditioning, are coordinated in part by nitric oxide ( NO). We tested the hypothesis that acute transient hypoxia stimulates NO synthase ( NOS)-activated mechanisms of mitochondrial biogenesis in the hypoxia-sensitive subcortex of wild-type ( Wt) and neuronalNOS( nNOS) and endothelial NOS ( eNOS)-deficient mice. Mice were exposed to hypobaric hypoxia for 6 h, and changes in immediate hypoxic transcriptional regulation of mitochondrial biogenesis was assessed in relation to mitochondrial DNA( mtDNA) content and mitochondrial density. There were no differences in cerebral blood flow or hippocampal P0(2) responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, localized in reporter mice expressing mitochondrial green fluorescence protein, were seen primarily in hippocampal neurons. eNOS(-/-) mice displayed lower basal levels but maintained hypoxic induction of these transcripts. In contrast, nuclear transcriptional regulation of mitochondrial biogenesis in nNOS(-/-) mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt and eNOS(-/-) mice but not in nNOS(-/-) mice. Hypoxia stimulated PGC-1 alpha protein expression and phosphorylation of protein kinase A and cAMP response element binding ( CREB) protein in Wt mice, but CREB only was activated in eNOS(-/-) mice and not in nNOS(-/-) mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1 alpha and CREB.