Department of Pediatrics II, Medical University Innsbruck Innsbruck, Austria ; Tyrolean Cancer Research Institute Innsbruck, Austria.
Front Physiol. 2013 Jun 20;4:147. doi: 10.3389/fphys.2013.00147. eCollection 2013.
Forkhead box O (FOXO) transcription factors are regulators of cell-type specific apoptosis and cell cycle arrest but also control longevity and reactive oxygen species (ROS). ROS-control by FOXO is mediated by transcriptional activation of detoxifying enzymes such as Superoxide dismutase 2 (SOD2), Catalase or Sestrins or by the repression of mitochondrial respiratory chain proteins resulting in reduced mitochondrial activity. FOXO3 also regulates the adaptation to hypoxia by reducing mitochondrial mass and oxygen consumption during HIF-1α activation. In neuronal tumor cells, FOXO3 triggers ROS-accumulation as a consequence of transient mitochondrial outer membrane permeabilization, which is essential for FOXO3-induced apoptosis in these cells. Cellular ROS levels are affected by the FOXO-targets Bim, BclxL, and Survivin. All three proteins localize to mitochondria and affect mitochondrial membrane potential, respiration and cellular ROS levels. Bim-activation by FOXO3 causes mitochondrial depolarization resulting in a transitory decrease of respiration and ROS production. Survivin, on the other hand, actively changes mitochondrial architecture, respiration-efficacy and energy metabolism. This ability distinguishes Survivin from other anti-apoptotic proteins such as BclxL, which inhibits ROS by inactivating Bim but does not alter mitochondrial function. Importantly, FOXO3 simultaneously also activates ROS-detoxification via induction of SESN3. In this paper we discuss the hypothesis that the delicate balance between ROS-accumulation by Bim-triggered mitochondrial damage, mitochondrial architecture and ROS-detoxifying proteins determines cell fate. We provide evidence for a FOXO self-reactivating loop and for novel functions of FOXO3 in controlling mitochondrial respiration of neuronal cells, which further supports the current view that FOXO transcription factors are information-integrating sentinels of cellular stress and critical modulators of cell homeostasis.
叉头框 O (FOXO) 转录因子是细胞类型特异性凋亡和细胞周期阻滞的调节剂，但也控制着寿命和活性氧 (ROS)。FOXO 通过转录激活解毒酶，如超氧化物歧化酶 2 (SOD2)、过氧化氢酶或 Sestrins，或通过抑制线粒体呼吸链蛋白来控制 ROS，从而减少线粒体活性。FOXO3 还通过减少线粒体质量和耗氧量来调节对低氧的适应，从而在 HIF-1α激活期间。在神经肿瘤细胞中，FOXO3 作为瞬时线粒体外膜通透性的结果引发 ROS 积累，这对于这些细胞中 FOXO3 诱导的凋亡是必不可少的。细胞内 ROS 水平受 FOXO 靶标 Bim、BclxL 和 Survivin 的影响。这三种蛋白都定位于线粒体，并影响线粒体膜电位、呼吸和细胞内 ROS 水平。FOXO3 通过激活 Bim 导致线粒体去极化，从而导致呼吸和 ROS 产生短暂下降。另一方面，Survivin 积极改变线粒体结构、呼吸效率和能量代谢。这种能力使 Survivin 区别于其他抗凋亡蛋白，如 BclxL，BclxL 通过失活 Bim 抑制 ROS，但不改变线粒体功能。重要的是，FOXO3 同时通过诱导 SESN3 来激活 ROS 解毒。在本文中，我们提出了一个假设，即由 Bim 触发的线粒体损伤、线粒体结构和 ROS 解毒蛋白之间的微妙平衡决定了细胞命运。我们提供了 FOXO 自我激活环的证据，以及 FOXO3 控制神经元细胞线粒体呼吸的新功能，这进一步支持了当前的观点，即 FOXO 转录因子是细胞应激的信息整合哨兵和细胞内稳态的关键调节剂。
