Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells.
Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells.
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DOI：
10.1016/j.freeradbiomed.2014.01.004
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发表时间：
2014-04
影响因子：
7.4
通讯作者：
Handa, James T.
中科院分区：
文献类型：
--
作者：
Cano, Marisol;Wang, Lei;Wan, Jun;Barnett, Bradley P.;Ebrahimi, Katayoon;Qian, Jiang;Handa, James T.
关键词：
在衰老相关疾病中，细胞是如何从氧化应激中退化的还不完全清楚。这项研究的目的是确定氧化应激激活的关键细胞保护途径，并确定它们的保护程度。使用无偏见的策略和微阵列分析，经香烟烟雾提取物(CSE)处理的视网膜色素上皮(RPE)细胞具有参与抗氧化剂和未折叠蛋白反应(UPR)的过度表达基因。差异表达的抗氧化剂基因主要位于细胞质中，没有诱导线粒体中的超氧化物和过氧化氢的中和基因，导致超氧化物的积累和ATP的产生减少。同时，CSE诱导了包括CHOP在内的UPR传感器IRE1α、p-PERK和ATP6，由于CHOP基因敲除降低了细胞存活率，因此具有细胞保护作用。在玻璃体内注射CSE的小鼠，视网膜色素上皮增加了IRE1ATP，降低了α，并发生了上皮向间充质的转变，这表明LRAT丰度降低，ZO1免疫标记改变，细胞形态异常。早期AMD患者轻度变性的视网膜色素上皮有明显的IRE1α，但线粒体TOM2 0免疫标记很少。虽然氧化应激被认为是通过线粒体和内质网之间的合作来诱导抗氧化反应，但在这里，我们发现尽管存在保护性的UPR，线粒体仍然受到足够的损害，可以诱导上皮细胞向间充质细胞的转变。在早期AMD样本中也有类似的反应，这些结果表明线粒体容易受到氧化应激的影响，尽管在衰老相关疾病的早期阶段有保护性的UPR。
How cells degenerate from oxidative stress in aging-related disease is incompletely understood. The study’s intent was to identify key cytoprotective pathways activated by oxidative stress, and determine the extent of their protection. Using an unbiased strategy with microarray analysis, retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had over-represented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, and developed epithelial-mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early AMD samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. While oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and ER, herein, we show that mitochondria become impaired sufficiently to induce epithelial-mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during early phases of aging-related disease.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
4.2
作者：
Feher, Janos;Kovacs, Illes;Gabrieli, Corrado Balacco
通讯作者：
Gabrieli, Corrado Balacco
影响因子：
--
作者：
Kassoff, A;Kassoff, J;Chew, EY
通讯作者：
Chew, EY
影响因子：
4.8
作者：
Halterman, Marc W.;Gill, Molly;Federoff, Howard J.
通讯作者：
Federoff, Howard J.
影响因子：
--
作者：
FORUS, A;FLORENES, VA;MYKLEBOST, O
通讯作者：
MYKLEBOST, O