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Diabetic retinopathy (DR) is the most significant microvascular complication of diabetes leading to blindness. However, treatment of DR remains challenging due to the lack of effective therapies, particularly in its early stages. In this study, we found that expression of the mitochondrial peptide 12S rRNA-c (MOTS-c) is localized predominantly in retinal endothelial cells. Therefore, we combined genetic and pharmacological methods in vivo and in vitro to investigate whether vascular endothelial loss in DR is associated with MOTS-c dysregulation and its potential mechanisms. High glucose exposure reduced MOTS-c expression in retinal vessels. MOTS-c treatment protected the endothelial barrier and ameliorated mitochondrial dysfunction in high glucose-induced damaged human retinal endothelial cells and in streptozocin-induced diabetic mouse models. Furthermore, in vitro experiments allowed us to explore potential molecular mechanisms by which MOTS-c repairs vascular endothelial damage. Transcriptomic and lipidomic analyses revealed that MOTS-c can increase phospholipase A2 activity and regulate phospholipid metabolism. Among the differentially expressed genes associated with increased phospholipase A2 activity, the phospholipase A2 group VI gene (PLA2G6) showed the most significant increase after MOTS-c treatment. PLA2G6-mediated lipid peroxidation is a major mechanism of retinal endothelial barrier protection during MOTS-c treatment, while downregulation of PLA2G6 expression blocks the protective effect of MOTS-c against vascular endothelial damage in vitro and in vivo. Thus, our results reveal a novel role for MOTS-c dysregulation in mediating vascular endothelial injury in diabetic retinopathy (DR), and MOTS-c supplementation is a potential therapeutic approach that can regulate phospholipid homeostasis and protect the endothelial barrier from injury in DR via PLA2G6.
We thank the Department of Rheumatology and Immunology of Nanjing Drum Tower Hospital for providing consultation and equipment, which played an important role in supporting this study.
This study was supported by the Basic Research Program of Jiangsu Province (Project Nos. BK20250232 and BK20251719), the China Postdoctoral Research Foundation (Project No. 2025M782072), the Support Program for Outstanding Postdoctoral Researchers of Jiangsu Province (Project No. 2025ZB881), and the Open Project of Integrated Research of Traditional Chinese and Western Medicine of Institute of Chinese Medicine, Nanjing University (Project No. ICMN2024003).
Department of Ophthalmology, Gulou Hospital Affiliated to Nanjing University School of Medicine, Nanjing, China.
Department of Ophthalmology, The Fifth People’s Hospital of Wuxi Affiliated with Jiangnan University, Wuxi, China.
Department of Rheumatology and Immunology, Affiliated Hospital of Nanjing University Medical School, Gulou Hospital, Nanjing, China.
Nanjing, China; Clinical College of Nanjing Medical University; Department of Ophthalmology, Nanjing Drum Tower Hospital.
Department of Ophthalmology, Nanjing Drum Tower Hospital Affiliated to Nanjing Clinical College of Chinese Medicine, China.
All animal experiments were performed in accordance with institutional guidelines and were approved by the Animal Ethics Committee of Nanjing Drum Tower Hospital, approval number 2025AE01076.
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Liao Yi, Xiang Jie, Xia Yong, et al. Mitochondrial peptide MOTS-c restores vascular endothelial damage in diabetic retinopathy via PLA2G6. *Cell Death Discov.* (2026). https://doi.org/10.1038/s41420-026-03384-5
Post time: Oct-16-2026