Centre for Altitude, Space, and Extreme Environment Medicine, University College London (UCL) Institute of Child Health, University College London, London, UK.
FASEB J. 2012 Apr;26(4):1431-41. doi: 10.1096/fj.11-197772. Epub 2011 Dec 20.
Ascent to high altitude is associated with a fall in the partial pressure of inspired oxygen (hypobaric hypoxia). For oxidative tissues such as skeletal muscle, resultant cellular hypoxia necessitates acclimatization to optimize energy metabolism and restrict oxidative stress, with changes in gene and protein expression that alter mitochondrial function. It is known that lowlanders returning from high altitude have decreased muscle mitochondrial densities, yet the underlying transcriptional mechanisms and time course are poorly understood. To explore these, we measured gene and protein expression plus ultrastructure in muscle biopsies of lowlanders at sea level and following exposure to hypobaric hypoxia. Subacute exposure (19 d after initiating ascent to Everest base camp, 5300 m) was not associated with mitochondrial loss. After 66 d at altitude and ascent beyond 6400 m, mitochondrial densities fell by 21%, with loss of 73% of subsarcolemmal mitochondria. Correspondingly, levels of the transcriptional coactivator PGC-1α fell by 35%, suggesting down-regulation of mitochondrial biogenesis. Sustained hypoxia also decreased expression of electron transport chain complexes I and IV and UCP3 levels. We suggest that during subacute hypoxia, mitochondria might be protected from oxidative stress. However, following sustained exposure, mitochondrial biogenesis is deactivated and uncoupling down-regulated, perhaps to improve the efficiency of ATP production.
高原上升会导致吸入氧气的分压降低（低氧）。对于氧化组织，如骨骼肌，细胞缺氧需要适应以优化能量代谢并限制氧化应激，这会导致基因和蛋白质表达的变化，从而改变线粒体功能。已知从高海拔地区返回的低地居民的肌肉线粒体密度降低，但潜在的转录机制和时间过程尚不清楚。为了探索这些，我们在海平面和暴露于低压缺氧后测量了低地居民肌肉活检中的基因和蛋白质表达以及超微结构。亚急性暴露（从开始攀登珠穆朗玛峰大本营，海拔 5300 米后 19 天）与线粒体损失无关。在海拔 66 天后和海拔 6400 米以上上升后，线粒体密度下降了 21%，亚肌节线粒体损失了 73%。相应地，转录共激活因子 PGC-1α 的水平下降了 35%，表明线粒体生物发生的下调。持续缺氧还降低了电子传递链复合物 I 和 IV 和 UCP3 的表达水平。我们认为，在亚急性缺氧期间，线粒体可能免受氧化应激的影响。然而，在持续暴露后，线粒体生物发生被去激活，解偶联被下调，这可能是为了提高 ATP 产生的效率。
