Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Apoptosis. 2012 Nov;17(11):1156-69. doi: 10.1007/s10495-012-0758-6.
Aberrant levels of reactive oxygen species (ROS) rapidly generated from NADPH oxidase (NOX) activation can be cytotoxic due to activating pro-apoptotic signals. However, ROS also induce pro-survival autophagy through the engulfment of damaged mitochondria. This study is aimed at investigating the cytoprotective role of albumin against NOX/ROS-induced autophagy and apoptosis under serum starvation. Serum starvation induced apoptosis following a myeloid cell leukemia sequence 1 (Mcl-1)/Bax imbalance, loss of the mitochondrial transmembrane potential, and caspase activation accompanied by pro-survival autophagy following canonical inhibition of mammalian target of rapamycin complex 1 (mTORC1). Aberrant ROS generation, initially occurring through NOX, facilitated mitochondrial damage, autophagy, and apoptosis. Autophagy additionally regulated the accumulation of ROS-generating mitochondria. NOX/ROS permitted p38 mitogen-activated protein kinase (p38 MAPK)-regulated mitochondrial apoptosis, accompanied by non-canonical induction of autophagy. In addition, activation of glycogen synthase kinase (GSK)-3β by NOX/ROS-inactivated Akt facilitated a decrease in Mcl-1, followed by mitochondrial apoptosis as well as autophagy. Restoring albumin conferred an anti-oxidative effect against serum starvation-deregulated NOX, p38 MAPK, and Akt/GSK-3β/Mcl-1/caspase-3 signaling. Albumin also prevented autophagy by sustaining mTORC1. These results indicate an anti-oxidative role for albumin via preventing NOX/ROS-mediated mitochondrial signaling to stimulate apoptosis as well as autophagy. Autophagy, initially induced by canonical inhibition of mTORC1 and enhanced by non-canonical mitochondrial damage, acts physically as a pro-survival mechanism.
活性氧（ROS）水平异常，迅速从 NADPH 氧化酶（NOX）的激活产生可能由于激活促凋亡信号而具有细胞毒性。然而，ROS 也通过吞噬受损的线粒体诱导促存活自噬。本研究旨在研究白蛋白对血清饥饿时 NOX/ROS 诱导的自噬和凋亡的细胞保护作用。血清饥饿诱导髓样细胞白血病序列 1（Mcl-1）/Bax 失衡、线粒体跨膜电位丧失和半胱天冬酶激活后的细胞凋亡，随后经典抑制哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）诱导促存活自噬。异常 ROS 生成最初通过 NOX 发生，促进线粒体损伤、自噬和凋亡。自噬还调节产生 ROS 的线粒体的积累。NOX/ROS 允许 p38 丝裂原活化蛋白激酶（p38 MAPK）调节的线粒体凋亡，同时非经典诱导自噬。此外，NOX/ROS 激活糖原合酶激酶（GSK）-3β使 Akt 失活，促进 Mcl-1 减少，随后发生线粒体凋亡和自噬。恢复白蛋白对血清饥饿失调的 NOX、p38 MAPK 和 Akt/GSK-3β/Mcl-1/半胱天冬酶-3 信号具有抗氧化作用。白蛋白还通过维持 mTORC1 来防止自噬。这些结果表明，白蛋白通过防止 NOX/ROS 介导的线粒体信号转导来刺激凋亡和自噬，从而发挥抗氧化作用。自噬最初由 mTORC1 的经典抑制诱导，并通过非经典线粒体损伤增强，作为一种促存活机制发挥物理作用。
