Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Essays Biochem. 2010;47:69-84. doi: 10.1042/bse0470069.
Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer's disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.
虽然已经证实，体育活动会增加肌肉中的线粒体含量，但这一过程的分子机制直到最近才被阐明。线粒体功能障碍是与衰老相关的不同疾病（如 2 型糖尿病和阿尔茨海默病）的一个重要组成部分。PGC-1α（过氧化物酶体增殖物激活受体 γ共激活因子 1α）是一种共转录调节因子，通过激活不同的转录因子（包括核呼吸因子 1 和核呼吸因子 2）来诱导线粒体生物发生，从而激活线粒体转录因子 A。后者驱动线粒体 DNA 的转录和复制。PGC-1α 本身受到几种不同的关键因素的调节，这些因素将在本章中进行综述。其中，AMPK（AMP 激活的蛋白激酶）最为重要。AMPK 作为细胞的能量传感器，是线粒体生物发生的关键调节剂。AMPK 的活性随着年龄的增长而降低，这可能导致线粒体生物发生和功能随着衰老而减少。鉴于线粒体功能障碍在许多疾病的发病机制和衰老过程中可能具有重要作用，了解调节线粒体生物发生和功能的分子机制可能为潜在的重要治疗靶点提供依据。
