1. Neuroprotective role of retinal SIRT3 against acute photo-stress
- Author
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Kenya Yuki, Kazuo Tsubota, Jonathan B. Lin, Hideto Osada, Rajendra S. Apte, Shunsuke Kubota, Norimitsu Ban, Yoko Ozawa, Mitsuhiro Watanabe, and Eriko Toda
- Subjects
0301 basic medicine ,Retinal degeneration ,Aging ,Retinal Disorder ,Neuroprotection ,Article ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Retinal thinning ,chemistry.chemical_classification ,Reactive oxygen species ,Retina ,biology ,RC952-954.6 ,Retinal ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Geriatrics ,biology.protein ,sense organs ,Geriatrics and Gerontology ,030217 neurology & neurosurgery - Abstract
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., Author Summary 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.
- Published
- 2017