Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
Mitochondrion. 2012 Jan;12(1):86-99. doi: 10.1016/j.mito.2011.09.009. Epub 2011 Sep 29.
Over the past two decades, a complex nuclear transcriptional machinery controlling mitochondrial biogenesis and function has been described. Central to this network are the PGC-1 family coactivators, characterised as master regulators of mitochondrial biogenesis. Recent literature has identified a broader role for PGC-1 coactivators in both cell death and cellular adaptation under conditions of stress, here reviewed in the context of the pathology associated with cancer, neurodegeneration and cardiovascular disease. Moreover, we propose that these studies also imply a novel conceptual framework on the general role of mitochondrial dysfunction in disease. It is now well established that the complex nuclear transcriptional control of mitochondrial biogenesis allows for adaptation of mitochondrial mass and function to environmental conditions. On the other hand, it has also been suggested that mitochondria alter their function according to prevailing cellular energetic requirements and thus function as sensors that generate signals to adjust fundamental cellular processes through a retrograde mitochondria-nucleus signalling pathway. Therefore, altered mitochondrial function can affect cell fate not only directly by modifying cellular energy levels or redox state, but also indirectly, by altering nuclear transcriptional patterns. The current literature on such retrograde signalling in both yeast and mammalian cells is thus reviewed, with an outlook on its potential contribution to disease through the regulation of PGC-1 family coactivators. We propose that further investigation of these pathways will lead to the identification of novel pharmacological targets and treatment strategies to combat disease.
在过去的二十年中，人们已经描述了一个控制线粒体生物发生和功能的复杂核转录机制。这个网络的核心是 PGC-1 家族共激活剂，它们被认为是线粒体生物发生的主要调节因子。最近的文献还确定了 PGC-1 共激活剂在细胞死亡和应激条件下细胞适应中的更广泛作用，本文在与癌症、神经退行性疾病和心血管疾病相关的病理学背景下对此进行了综述。此外，我们还提出，这些研究也暗示了线粒体功能障碍在疾病中的一般作用的新概念框架。现在已经确立，线粒体生物发生的复杂核转录控制允许线粒体质量和功能适应环境条件。另一方面，也有人提出，线粒体根据当前细胞的能量需求改变其功能，因此作为传感器，通过逆行线粒体-核信号通路产生信号来调整基本的细胞过程。因此，改变线粒体功能不仅可以通过改变细胞能量水平或氧化还原状态直接影响细胞命运，而且还可以通过改变核转录模式间接影响细胞命运。因此，本文还综述了酵母和哺乳动物细胞中这种逆行信号的最新文献，并展望了其通过调节 PGC-1 家族共激活剂对疾病的潜在贡献。我们提出，进一步研究这些途径将有助于确定治疗疾病的新的药理学靶点和治疗策略。
