Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation
Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP-1-dependent energy deprivation
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DOI：
10.1096/fj.08-112375
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发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Hammerling, Ulrich
中科院分区：
文献类型：
--
作者：
Chiu, Haw-Jyh;Fischman, Donald A.;Hammerling, Ulrich
一个重要的未解决的问题是维生素A缺乏如何导致免疫缺陷，以及为什么维甲酸不能逆转免疫缺陷。当维生素A耗尽时，T细胞经历程序性细胞死亡（PCD），这是由视黄醇的天然竞争对手脱水视黄醇增强的。PCD不发生细胞凋亡，尽管发生共享的早期事件，包括线粒体膜去极化，渗透性转换孔开放，细胞色素c的释放。它也缺乏半胱天冬酶-3激活、染色质凝聚和核酸内切酶介导的DNA降解，这些都是凋亡的标志。维生素A剥夺后的PCD表现出活性氧（ROS）产生增加，ATP和NAD（+）水平急剧下降，聚（ADP-核糖）聚合酶（PARP）-1活化。这些后面的步骤是致病的，因为中和ROS，施加缺氧条件，或通过遗传或药理学方法抑制PARP-1可以防止能量消耗和PCD。这些数据突出了维生素A在线粒体能量稳态中的新的调节作用。- 赵，H. J.，Fischman，D.一、哈默林大学维生素A消耗导致氧化应激、线粒体功能障碍和PARP1依赖性能量剥夺。FASEB J. 22，3878 - 3887（2008）
A significant unresolved question is how vitamin A deprivation causes, and why retinoic acid fails to reverse, immunodeficiency. When depleted of vitamin A, T cells undergo programmed cell death (PCD), which is enhanced by the natural competitor of retinol, anhydroretinol. PCD does not happen by apoptosis, despite the occurrence of shared early events, including mitochondrial membrane depolarization, permeability transition pore opening, and cytochrome c release. It also lacks caspase-3 activation, chromatin condensation, and endonuclease-mediated DNA degradation, hallmarks of apoptosis. PCD following vitamin A deprivation exhibits increased production of reactive oxygen species (ROS), drastic reductions in ATP and NAD(+) levels, and activation of poly-(ADP-ribose) polymerase (PARP) -1. These latter steps are causative because neutralizing ROS, imposing hypoxic conditions, or inhibiting PARP-1 by genetic or pharmacologic approaches prevents energy depletion and PCD. The data highlight a novel regulatory role of vitamin A in mitochondrial energy homeostasis. -Chiu, H.-J., Fischman, D. A., Hammerling, U. Vitamin A depletion causes oxidative stress, mitochondrial dysfunction, and PARP1-dependent energy deprivation. FASEB J. 22, 3878-3887 (2008)