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Retinal neurodegeneration develops early in the course of diabetic retinopathy (DR), and our previous research showed that succinate accumulation results in retinal ganglion cells (RGCs) dysfunction in the retinas of rats with DR. Succinate can enhance lysine succinylation, but the succinylation of DR is not well understood. In this study, we investigated the role of the succinylome in DR and identified the key factor in this process. TMT labeling and LC–MS/MS analysis were combined to quantify the differentially succinylated proteins between vitreous humor (VH) samples from DR and non-DR patients. A total of 74 sites in 35 proteins were differentially succinylated between DR and non-DR vitreous humor samples, among which succinylation of the K108 site of optineurin (OPTN K108 su ) in the defense response was enriched by GO analysis based on the biological process category. Then, using a streptozotocin (STZ)-induced diabetic rat model, R28 cells and primary rat RGCs (rRGCs), we demonstrated that OPTN underwent lysine succinylation in the retinas of rats with DR and that OPTN K108 su  mediated autophagic flux blockade under high-glucose (HG) conditions. Sirt5 can desuccinylate OPTN K108 su , thus protecting RGCs function from high glucose-induced RGCs autophagic flux blockade in the diabetic retina. Overall, desuccinylation of OPTN is an essential adaptive mechanism for ameliorating autophagic flux blockade in RGCs under DR conditions, and targeting the Sirt5-desuccK108-OPTN axis may thus open an avenue for therapeutic intervention in RCGs dysfunction.

Sirt5-mediated desuccinylation of OPTN protects retinal ganglion cells from autophagic flux blockade in diabetic retinopathy