Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress.
Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress.
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DOI：
10.2147/chc.s4955
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Becker DF
中科院分区：
文献类型：
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作者：
Natarajan SK;Becker DF
黄素蛋白利用黄素单核苷酸或黄素腺嘌呤二核苷酸作为辅因子催化多种反应。黄素酶的氧化还原酶性质暗示它们参与氧化还原稳态、氧化应激和各种细胞过程，包括程序性细胞死亡。在这里，我们探讨了三个关键的黄素蛋白参与细胞凋亡和氧化还原信号，即，凋亡诱导因子（AIF），脯氨酸脱氢酶，NADPH氧化酶。这些蛋白质具有不同的生化功能，并通过独特的机制影响凋亡信号。AIF在凋亡信号传导中的作用是双重的，在细胞暴露于凋亡刺激物时，AIF将细胞内位置从线粒体内膜空间改变到细胞核。在线粒体中，AIF增强线粒体生物能量学和复合物I活性/组装，以帮助维持适当的细胞氧化还原稳态。在易位到细胞核后，AIF与其他蛋白质（如亲环素A）形成染色质降解复合物。AIF从线粒体易位到细胞核是由氧化应激触发的，这暗示AIF是线粒体氧化还原传感器。脯氨酸脱氢酶是一种膜结合的黄素酶，催化脯氨酸氧化的限速步骤。肿瘤抑制因子p53上调脯氨酸脱氢酶导致线粒体活性氧增强，从而诱导内源性凋亡途径。NADPH氧化酶是一组产生活性氧物质用于氧化应激和信号传导目的的酶。在激活时，NADPH氧化酶2在嗜中性粒细胞中产生超氧化物的爆发，导致在吞噬作用期间杀死微生物。NADPH氧化酶还参与氧化还原信号传导，其涉及过氧化氢介导的调节细胞增殖和细胞死亡的不同途径的活化。每种酶的潜在治疗策略也被强调。
Flavoproteins catalyze a variety of reactions utilizing flavin mononucleotide or flavin adenine dinucleotide as cofactors. The oxidoreductase properties of flavoenzymes implicate them in redox homeostasis, oxidative stress, and various cellular processes, including programmed cell death. Here we explore three critical flavoproteins involved in apoptosis and redox signaling, ie, apoptosis-inducing factor (AIF), proline dehydrogenase, and NADPH oxidase. These proteins have diverse biochemical functions and influence apoptotic signaling by unique mechanisms. The role of AIF in apoptotic signaling is two-fold, with AIF changing intracellular location from the inner mitochondrial membrane space to the nucleus upon exposure of cells to apoptotic stimuli. In the mitochondria, AIF enhances mitochondrial bioenergetics and complex I activity/assembly to help maintain proper cellular redox homeostasis. After translocating to the nucleus, AIF forms a chromatin degrading complex with other proteins, such as cyclophilin A. AIF translocation from the mitochondria to the nucleus is triggered by oxidative stress, implicating AIF as a mitochondrial redox sensor. Proline dehydrogenase is a membrane-associated flavoenzyme in the mitochondrion that catalyzes the rate-limiting step of proline oxidation. Upregulation of proline dehydrogenase by the tumor suppressor, p53, leads to enhanced mitochondrial reactive oxygen species that induce the intrinsic apoptotic pathway. NADPH oxidases are a group of enzymes that generate reactive oxygen species for oxidative stress and signaling purposes. Upon activation, NADPH oxidase 2 generates a burst of superoxide in neutrophils that leads to killing of microbes during phagocytosis. NADPH oxidases also participate in redox signaling that involves hydrogen peroxide-mediated activation of different pathways regulating cell proliferation and cell death. Potential therapeutic strategies for each enzyme are also highlighted.