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.

SIRT3是线粒体活性氧以及线粒体功能的关键调节剂。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预防视网膜神经变性至关重要。尽管以前的报道已经证明SIRT3在视网膜中高表达并且在神经保护中很重要，但是SIRT3在调节视网膜中活性氧的功能上还是未知的。在这项研究中，我们调查了SIRT3敲除小鼠在光诱导的视网膜变性模型中视网膜SIRT3的作用。我们证明SIRT3缺乏会导致急性的活性氧物质积累和光照后视网膜中的内质网应激，从而导致光感受器死亡增加，视网膜变薄和视网膜功能降低。使用感光细胞衍生的细胞系，我们揭示了活性氧是内质网应激的上游引发剂。在SIRT3敲低条件下，我们证明了降低的超氧化物歧化酶2活性导致升高的细胞内活性氧种类。这些研究有助于阐明SIRT3在感光神经元存活中的关键作用，并暗示SIRT3可能是氧化应激诱导的视网膜疾病的治疗靶标。