Autophagy Impairment in Retinal Ganglion Cells Following Hypoglycemia in Mice

TL;DR

This study shows that hypoglycemia increases autophagosome formation in retinal ganglion cells but disrupts their fusion with lysosomes, reducing autophagy's protective role and potentially contributing to diabetic retinopathy.

Contribution

The study reveals a novel mechanism of autophagy impairment in retinal ganglion cells under hypoglycemic conditions.

Findings

Hypoglycemia increases autophagosome formation in retinal ganglion cells.

Low-glucose conditions cause a defect in autophagosome/lysosome fusion in isolated retinal ganglion cells.

Autophagy's protective effect is inhibited due to impaired fusion, potentially worsening diabetic retinopathy.

Abstract

What are the main findings?

The formation of autolysosomes is increased by hypoglycemia both in living tissue and in retinal ganglion cells (RGCs).

Hypoglycemia induces a defect in the autophagosome/lysosomes fusion process in isolated RGC, removing the protective effect of autophagy.

What is the implication of the main finding?

Modulating the autophagy process may help to prevent complications associated with diabetic retinopathy (DR).

(1) Background: Diabetic retinopathy (DR), caused by hypo- and hyperglycaemia, is the leading cause of blindness. Hypoglycemia induces endoplasmic reticulum stress and retinal cell death in mice, and low-glucose conditions induce macroautophagy/autophagy defects in 661W photoreceptor cells and retinal explants. Very few studies have analyzed the effect of hypoglycemia on retinal autophagy, so we decided to fill this gap. (2) Methods: We use C57BL/6 and GFP-LC3 mice and isolated retinal ganglion cells (RGCs) from both mouse models to study the autophagy process. (3) Results: Intraocular injection of rapamycin and 5 h hypoglycemia showed an increase in autophagosomes formation, specifically in the RGCs. Isolated GFP-LC3 RGCs showed an increase in autophagosome formation under low-glucose conditions. In contrast, infection of isolated C57BL/6 RGCs with the RFP-GFP-LC3 lentivirus revealed a defect in autophagosome/lysosome fusion under these conditions. (4) Conclusions: This study showed that 5 h hypoglycemia induces autophagosomes formation in mouse RGCs; however, a defect in the fusion process inhibits the protective effect of autophagy. Therefore, modulating both autophagic and apoptotic pathways might be important to avoid complications associated with DR.

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