Gutsaeva D R, Suliman H B, Carraway M S, Demchenko I T, Piantadosi C A
Department of Medicine and Anesthesiology and Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Box 3315, Durham, NC 27710, USA.
Neuroscience. 2006;137(2):493-504. doi: 10.1016/j.neuroscience.2005.07.061. Epub 2005 Nov 17.
The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity of nuclear and mitochondrial transcription factors for mitochondrial DNA replication was tested in the in vivo rat brain. Mitochondrial reactive oxygen species generation was stimulated using pre-convulsive doses of hyperbaric oxygen and hippocampal mitochondrial DNA content and neuronal and mitochondrial morphology and cell proliferation were evaluated at 1, 5 and 10 days. Gene expression was subsequently evaluated to assess nuclear and mitochondrial-encoded respiratory genes, mitochondrial transcription factor A, and nuclear respiratory transcription factors-1 and -2. After 1 day, a mitochondrial DNA deletion emerged involving Complex I and IV subunit-encoding regions that was independent of overt neurological or cytological O(2) toxicity, and resolved before the onset of cell proliferation. This damage was attenuated by blockade of neuronal nitric oxide synthase. Compensatory responses were found in nuclear gene expression for manganese superoxide dismutase, mitochondrial transcription factor A, and nuclear respiratory transcription factor-2. Enhanced nuclear respiratory transcription factor-2 binding activity in hippocampus was accompanied by a nearly three-fold boost in mitochondrial DNA content over 5 days. The finding that O(2) activates regional mitochondrial DNA transcription, replication, and mitochondrial biogenesis in the hippocampus may have important implications for maintaining neuronal viability after brain injury.
活性氧对线粒体DNA的损伤会增加参与线粒体DNA复制的核转录因子和线粒体转录因子的活性，这一假说在大鼠活体脑中得到了验证。使用惊厥前剂量的高压氧刺激线粒体活性氧的产生，并在第1、5和10天评估海马体线粒体DNA含量、神经元及线粒体形态以及细胞增殖情况。随后评估基因表达，以检测核编码和线粒体编码的呼吸基因、线粒体转录因子A以及核呼吸转录因子-1和-2。1天后，出现了涉及复合体I和IV亚基编码区域的线粒体DNA缺失，该缺失与明显的神经或细胞O(2)毒性无关，并在细胞增殖开始前得到修复。神经元型一氧化氮合酶的阻断减弱了这种损伤。在锰超氧化物歧化酶、线粒体转录因子A和核呼吸转录因子-2的核基因表达中发现了代偿性反应。海马体中增强的核呼吸转录因子-2结合活性伴随着5天内线粒体DNA含量近三倍的增加。O(2)激活海马体区域线粒体DNA转录、复制和线粒体生物合成这一发现，可能对脑损伤后维持神经元活力具有重要意义。
