Wang David B, Kinoshita Chizuru, Kinoshita Yoshito, Morrison Richard S
Department of Neurological Surgery, University of Washington School of Medicine, Box 356470, Seattle, WA 98195-6470, USA.
Department of Neurological Surgery, University of Washington School of Medicine, Box 356470, Seattle, WA 98195-6470, USA.
Biochim Biophys Acta. 2014 Aug;1842(8):1186-97. doi: 10.1016/j.bbadis.2013.12.015. Epub 2014 Jan 8.
The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be confirmed in neurons. Nonetheless, as mitochondria are essential for supporting normal neuronal functions and in initiating/propagating cell death signaling, it appears certain that the mitochondria-related functions of p53 will have broader implications than previously thought in acute and progressive neurological conditions, providing new therapeutic targets for treatment.
p53肿瘤抑制蛋白作为细胞对多种应激（包括DNA损伤、氧化和营养应激、缺血以及核仁功能破坏）的感受器，在决定细胞存活和死亡方面发挥着核心作用。p53依赖性凋亡的激活通过内在和外在途径导致线粒体凋亡变化，最显著的是通过细胞色素c的释放和半胱天冬酶级联反应的激活触发细胞死亡执行。尽管以前认为p53仅通过转录依赖性机制诱导线粒体凋亡变化，但最近的研究表明，p53还通过在线粒体的转录非依赖性作用来调节凋亡。最近的证据进一步表明，p53可以调节坏死性细胞死亡和自噬活性，包括线粒体自噬。越来越多参与线粒体代谢和呼吸的胞质和线粒体蛋白受p53调节，这也影响线粒体活性氧的产生。细胞氧化还原稳态也通过p53对促氧化和抗氧化蛋白表达的调节而直接受到调控。通过分裂和融合对线粒体大小和形状进行适当调节，可确保最佳的线粒体生物能量功能，同时实现足够的线粒体运输，以适应神经元结构特有的局部能量需求。线粒体动力学的异常调节越来越多地与神经退行性变有关，其中p53水平升高可能有直接作用，因为一些分裂/融合蛋白的表达直接受p53调控。因此，p53对线粒体完整性和功能的影响可能比其通过转录诱导线粒体凋亡的既定能力所预期的要广泛得多。然而，许多证明p53可通过核、胞质或线粒体内作用位点影响线粒体的证据尚未在神经元中得到证实。尽管如此，由于线粒体对于支持正常神经元功能以及启动/传播细胞死亡信号至关重要，p53与线粒体相关的功能在急性和进行性神经疾病中的影响似乎肯定比以前认为的更广泛，为治疗提供了新的治疗靶点。
