Acrylamide induces mitochondrial dysfunction and apoptosis in BV-2 microglial cells
Acrylamide induces mitochondrial dysfunction and apoptosis in BV-2 microglial cells
复制标题
丙烯酰胺诱导 BV-2 小胶质细胞线粒体功能障碍和凋亡
DOI：
10.1016/j.freeradbiomed.2015.03.013
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发表时间：
2015-07-01
影响因子：
7.4
通讯作者：
Liu, Xuebo
中科院分区：
文献类型：
--
作者：
Liu, Zhigang;Song, Ge;Liu, Xuebo
丙烯酰胺（ACR）是食品加工过程中产生的一种神经毒素。本研究检测了ACR在永生化小鼠小胶质细胞系BV 2中的氧化还原依赖性凋亡和炎症反应。BV 2细胞暴露于ACR以浓度依赖性方式降低细胞活力并诱导凋亡。ACR通过减少线粒体呼吸、无氧糖酵解和降低复合物I、III和IV亚基的表达来损害细胞能量代谢。线粒体功能障碍与线粒体膜电位和Bcl-2/Bax比值的降低有关，从而导致了线粒体驱动的凋亡信号的激活。这是伴随着（a）。调节氧化还原敏感性信号传导，抑制Akt活化和增加JNK和p38活化，和（b）增加NF κ B和下游诱导型一氧化氮合酶（iNOS）的表达和一氧化氮产生，从而间接支持ACR的促炎作用。nrf 2的表达也增加，但其易位到细胞核。预期的是，ACR对GSH的亲电攻击导致GSH的大量损失和少量GSSG的形成。ACR引起的细胞氧化还原状态的这些变化导致H2 O2形成增加。N-乙酰-L-半胱氨酸（NAC）可逆转ACR引起的线粒体功能和复合亚基表达的变化。同样，NAC通过增加GSH水平并伴随H2 O2产生的衰减来恢复细胞的氧化还原状态;这些作用导致细胞凋亡和炎症反应减少。ACR介导的线粒体功能障碍沿着更氧化的氧化还原状态似乎是导致内在凋亡途径和炎症反应激活的关键事件。(C)2015 Elsevier Inc. All rights reserved.
Acrylamide (ACR), a potent neurotoxin, can be produced during food processing at high temperature. This study examined the redox-dependent apoptotic and inflammatory responses of ACR in an immortalized mouse microglia cell line BV2. The exposure of BV2 cells to ACR reduced cell viability and induced apoptosis in a concentration-dependent manner. ACR impaired cell energy metabolism by decreasing mitochondrial respiration, anaerobic glycolysis, and lowering expression of the complex I, Ill, and IV subunits. Mitochondrial dysfunction was associated with a decrease of the mitochondrial membrane potential and the Bcl-2/Bax ratio, thus resulting in activation of the mitochondrion-driven apoptotic signaling. This was accompanied by (a). the modulation of redox-sensitive signaling, suppressed Akt activation and increased JNK and p38 activation, and (b) increased expression of NF kappa B and downstream inducible nitric oxide synthase (iNOS) and nitric oxide generation, thus supporting indirectly a proinflammatory effect of ACR. Nrf2 expression was also increased but not its translocation to the nucleus. Expectedly, the electrophilic attack of ACR on GSH resulted in substantial loss of GSH with a minor GSSG formation. These changes in the cell's redox status elicited by ACR resulted in increased H2O2 formation. The changes in mitochondrial functionality and complex subunit expression caused by ACR were reversed by N-acetyl-L-cysteine (NAC). Likewise, NAC restored the cell's redox status by increasing GSH levels with concomitant attenuation of H2O2 generation; these effects resulted in decreased apoptotic cell death and inflammatory responses. ACR-mediated mitochondrial dysfunction along with a more oxidized redox status seems to be critical events leading to activation of the intrinsic apoptotic pathway and inflammatory responses. (C) 2015 Elsevier Inc. All rights reserved.