Neuroprotective role of retinal SIRT3 against acute photo-stress

Norimitsu Ban,Kenya Yuki,Mitsuhiro Watanabe,Rajendra S Apte,Kazuo Tsubota,Yoko Ozawa,Shunsuke Kubota,Eriko Toda,Jonathan B Lin,Hideto Osada

doi:10.1038/s41514-017-0017-8

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.

Highlights

Sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, which modulate various metabolic responses affecting aging and longevity.[1]
We demonstrated increased acetylation of mitochondrial proteins isolated from SIRT3 KO retinas (Fig. 2a), indicating that SIRT3 acts as a deacetylase in the retina as it does in other tissues and organs.[4,5,6]
We found that endoplasmic reticulum (ER) stress markers such as Binding immunoglobulin protein (Bip) and C/EBP homologous protein (Chop) were significantly increased in SIRT3 KO retinas 1 h after the light exposure compared with WT retinas (Fig. 5e,f)

Summary

Introduction

Sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, which modulate various metabolic responses affecting aging and longevity.[1] We have previously reported that all seven sirtuins are highly expressed in the retina and that their expression varied with light–dark conditions.[2]. SIRT3, SIRT4, and SIRT5 regulate the activity of mitochondrial enzymes and drive metabolic cycles.[3,4] In particular, SIRT3 is considered a key regulator of mitochondrial functions.[4,5,6] Initial studies revealed that SIRT3 knockout (KO) mice showed significantly increased mitochondrial protein acetylation in the liver, there was no obvious systemic phenotype at baseline.[4].

Methods

Results

Conclusion