Neuroprotective role of retinal SIRT3 against acute photo-stress

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.

AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration

“…As shown in Fig. 8 , SIRT3 and SOD2 are widely expressed in the retina, consistent with previous studies [ 19 , 77 , 78 ], and AIBP may contribute to SIRT3-SOD2-mediated protection of retinal structure and cells against oxidative stress. Under oxidative stress conditions, multiple MAPK signaling pathways, including p38 and ERK1/2, are activated [ 51 , 52 ].…”

Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

“…SIRT1 was shown to negatively regulate the mTOR signaling (Ghosh et al, 2010) and this study revealed an inverse correlation between differential regulation of Sirtuin and mTOR signaling at higher concentrations of 25 μM peptide in the photoreceptor cells (Figure 4B). More recently, SIRT3, a key component of sirtuin signaling has been shown to impart neuroprotection against light toxicity in the retina and its suppression led to increased ROS production in 661 W cells (Ban et al, 2017).…”

Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes

“…Furthermore, we found that germline deletion of neither SIRT3 nor SIRT5 individually affected the progression of retinal dysfunction in the STZ-induced model of type 1 diabetes, while combined germline deletion of both SIRT3 and SIRT5 was associated with inner retinal dysfunction under hyperglycemic conditions. In contrast, single SIRT3 germline knockout mice themselves are more vulnerable to light-induced degeneration compared to wild-type controls 27 and SIRT3/SIRT5 double knockout mice are even more vulnerable compared to either single knockout 23 . These contrasting findings confirm that although there are some similarities in the underlying pathophysiology modeled by light-induced degeneration and STZ-induced hyperglycemia, there are also differences in the cell stress and death pathways that are activated by photopic stimuli versus hyperglycemic stress.…”

“…Therefore, the motivation behind this study was to test whether there was a neuroprotective role for metabolic regulation via NAMPT-mediated NAD + biosynthesis, SIRT3, or SIRT5 in a mouse model of type 1 diabetes. We have previously identified that NAMPT-mediated NAD + biosynthesis is important for retinal energy homeostasis and that both SIRT3 and SIRT5 are important for protecting the retina against light-induced degeneration 23,27 . In the current study, we found that although these pathways have important roles in regulating some facets of retinal homeostasis, they individually play only minimal neuroprotective roles in retinopathy in a mouse model of type 1 diabetes.…”