Abstract / Summary
Abstract As the predominant microvascular complication of diabetes mellitus that leads to blindness, diabetic retinopathy (DR) still presents a challenge due to the scarcity of effective therapeutic approaches, particularly in its early stage. Here, we observed that the expression of the mitochondrial open-reading-frame of the 12 S rRNA-c (MOTS-c), a mitochondrial-derived peptide, was predominantly localized in retinal endothelial cells. Thus, we combined genetic and pharmacological approaches in vivo and in vitro to explore whether vascular endothelial damage in DR is involved in MOTS-c dysregulation and its underlying mechanism. High glucose exposure reduced the expression of MOTS-c in retinal vasculature. While MOTS-c treatment protected endothelial barrier and ameliorated mitochondrial dysfunction in human retinal endothelial cells with high-glucose-induced injury and streptozotocin-induced diabetic mouse model. Furthermore, in vitro experiments were used to explore the underlying molecular mechanisms for rescuing vascular endothelial damage of MOTS-c. Transcriptomic analyses and lipidomic analyses showed that MOTS-c increased the phospholipase A2 activity and regulated phospholipid metabolism. Among the differentially expressed genes associated with upregulated phospholipase A2 activity, phospholipase A2 group VI (PLA2G6) exhibited the most significant upregulation following MOTS-c treatment. PLA2G6-mediated lipid peroxide degradation served as a primary mediator of protecting the retinal endothelial barrier during MOTS-c treatment, while knockdown of PLA2G6 blocked the protective effect of MOTS-c against vascular endothelial damage in vitro and in vivo. Taken together, our findings identified a novel role of MOTS-c dysregulation mediating vascular endothelial damage in DR and that MOTS-c supplementation was a potential therapeutic approach to regulating phospholipid homeostasis and protecting the endothelial barrier via PLA2G6 against DR.