Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury.
Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury.
复制标题
缺氧缺血性脑损伤后神经元线粒体生物发生迅速增加
DOI：
10.1161/strokeaha.108.520114
复制
发表时间：
2008-11
期刊：
影响因子：
8.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Yin W;Signore AP;Iwai M;Cao G;Gao Y;Chen J
线粒体的生物发生是通过细胞核和线粒体基因组的协调作用来调节的，以确保细胞器定期得到补充。这种高度调控的过程已经在骨骼肌和心肌中得到了很好的定义，但它在神经元细胞中的作用，特别是在应激或损伤下的作用，还没有得到很好的理解。在这项研究中，我们首次报道了大鼠新生儿缺氧/缺血性脑损伤（H-I）模型中线粒体生物发生的快速增加。出生后第7天大鼠单侧颈动脉结扎诱导H-I，随后缺氧2.5小时。H-I后各时间点采用长片段PCR半定量测定脑线粒体DNA （mtDNA）的相对量。Western blot检测HSP60和COXIV蛋白。Western blot和RT-PCR检测了线粒体生物发生转录调控的三个关键基因，过氧化物酶体增殖物激活受体共激活因子-1 （PGC-1）、核呼吸因子-1 （NRF-1）和线粒体转录因子A （TFAM）的表达。脑mtDNA含量在H-I后6小时显著升高，并持续升高至H-I后24小时。H-I后皮质梗死边界区神经元线粒体dna含量、线粒体数量、HSP60和COXIV蛋白及柠檬酸合成酶活性均升高，与时间变化平行。此外，在H-I后6 ~ 24小时，皮层NRF-1和TFAM的表达增加，而PGC-1没有变化。新生儿H-I脑损伤迅速诱导线粒体生物发生，这可能是脑内源性修复机制的一个新组成部分。
Mitochondrial biogenesis is regulated through the coordinated actions of both nuclear and mitochondrial genomes to ensure that the organelles are replenished on a regular basis. This highly regulated process has been well defined in skeletal and heart muscle, but its role in neuronal cells, particularly when under stress or injury, is not well understood. In this study, we report for the first time rapidly increased mitochondrial biogenesis in a rat model of neonatal hypoxic/ischemic brain injury (H-I). Postnatal day 7 rats were subjected to H-I induced by unilateral carotid artery ligation followed by 2.5 hours of hypoxia. The relative amount of brain mitochondrial DNA (mtDNA) was measured semiquantitatively using long fragment PCR at various time points after H-I. HSP60 and COXIV proteins were detected by Western blot. Expression of three genes critical for the transcriptional regulation of mitochondrial biogenesis, peroxisome proliferator-activated receptor coactivator-1 (PGC-1), nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM), were examined by Western blot and RT-PCR. Brain mtDNA content was markedly increased 6 hours after H-I, and continued to increase up to 24 hours after H-I. Paralleling the temporal change in mtDNA content, mitochondrial number and proteins HSP60 and COXIV, and citrate synthase activity were increased in neurons in the cortical infarct border zone after H-I. Moreover, cortical expression of NRF-1 and TFAM were increased 6 to 24 hours after H-I, whereas PGC-1 was not changed. Neonatal H-I brain injury rapidly induces mitochondrial biogenesis, which may constitute a novel component of the endogenous repair mechanisms of the brain.