Neuroprotective role of retinal SIRT3 against acute photo-stress.
Neuroprotective role of retinal SIRT3 against acute photo-stress.
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DOI：
10.1038/s41514-017-0017-8
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发表时间：
2017
影响因子：
5
通讯作者：
Tsubota K
中科院分区：
文献类型：
--
作者：
Ban N;Ozawa Y;Osada H;Lin JB;Toda E;Watanabe M;Yuki K;Kubota S;Apte RS;Tsubota K
SIRT3是线粒体活性氧以及线粒体功能的关键调节因子。视网膜是能量需求最高的组织之一，其中活性氧的调节对于防止视网膜神经变性至关重要。尽管先前的报道已经证明SIRT3在视网膜中高度表达并且在神经保护中重要，但是SIRT3在调节视网膜中的活性氧的功能在很大程度上是未知的。在这项研究中，我们使用SIRT3基因敲除小鼠研究了视网膜SIRT3在光诱导视网膜变性模型中的作用。我们证明，SIRT3缺乏导致急性活性氧积累和内质网应激在视网膜中的光暴露后，这导致增加感光细胞死亡，视网膜变薄，视网膜功能下降。使用光感受器衍生的细胞系，我们发现，活性氧是上游启动内质网应激。在SIRT3敲低条件下，我们证明了超氧化物歧化酶2活性的降低导致细胞内活性氧的升高。这些研究有助于阐明SIRT3在感光神经元存活中的关键作用，并表明SIRT3可能是氧化应激诱导的视网膜疾病的治疗靶点。Sirtuins是烟酰胺腺嘌呤二核苷酸依赖性蛋白脱乙酰酶。在七种sirtuins中，SIRT3是线粒体功能的关键调节因子。然而，SIRT3在视网膜中的功能在很大程度上是未知的。本研究探讨了视网膜SIRT3在光诱导视网膜变性小鼠模型中的作用，发现SIRT3在视网膜中具有神经保护作用。我们证明，SIRT3缺乏导致急性活性氧积累和内质网应激在视网膜中的光暴露后，这导致增加感光细胞死亡，视网膜变薄，视网膜功能下降。使用光感受器衍生的细胞系，我们发现，活性氧是内质网应激的上游启动子，超氧化物歧化酶2活性降低导致细胞内活性氧升高。这些结果表明SIRT3可能是氧化应激诱导的视网膜疾病的治疗靶点。
SIRT3 is a key regulator of mitochondrial reactive oxygen species as well as mitochondrial function. The retina is one of the highest energy-demanding tissues, in which the regulation of reactive oxygen species is critical to prevent retinal neurodegeneration. Although previous reports have demonstrated that SIRT3 is highly expressed in the retina and important in neuroprotection, function of SIRT3 in regulating reactive oxygen species in the retina is largely unknown. In this study, we investigated the role of retinal SIRT3 in a light-induced retinal degeneration model using SIRT3 knockout mice. We demonstrate that SIRT3 deficiency causes acute reactive oxygen species accumulation and endoplasmic reticulum stress in the retina after the light exposure, which leads to increased photoreceptor death, retinal thinning, and decreased retinal function. Using a photoreceptor-derived cell line, we revealed that reactive oxygen species were the upstream initiators of endoplasmic reticulum stress. Under SIRT3 knockdown condition, we demonstrated that decreased superoxide dismutase 2 activity led to elevated intracellular reactive oxygen species. These studies have helped to elucidate the critical role of SIRT3 in photoreceptor neuronal survival, and suggest that SIRT3 might be a therapeutic target for oxidative stress-induced retinal disorders. Sirtuins are nicotinamide adenine dinucleotide-dependent protein deacetylases. Among seven sirtuins, SIRT3 is a key regulator of mitochondrial function. However, functions of SIRT3 in the retina are largely unknown. In this study, we investigated the role of retinal SIRT3 in a mouse model of light-induced retinal degeneration, found that SIRT3 has neuroprotective role in the retina. We demonstrate that SIRT3 deficiency causes acute reactive oxygen species accumulation and endoplasmic reticulum stress in the retina after the light exposure, which leads to increased photoreceptor death, retinal thinning, and decreased retinal function. Using a photoreceptor-derived cell line, we revealed that reactive oxygen species were the upstream initiators of endoplasmic reticulum stress, and decreased superoxide dismutase 2 activity led to elevated intracellular reactive oxygen species. These results suggest that SIRT3 might be a therapeutic target for oxidative stress-induced retinal disorders.