Research progress on metabolic memory in diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Meng Lina ¹ ,  Zou Haidong ²

1. Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
2. Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Eye Disease Prevention and Treatment Center/Shanghai Eye Hospital, Shanghai Engineering Research Center of Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200080, China;

Corresponding author：

Zou Haidong, Email: zouhaidong@sjtu.edu.cn

Keywords：

Mitochondrial DNA methylation; Metabolic memory; Diabetic retinopathy; Epigenetics; Therapeutic targets; Review

DOI：

10.3760/cma.j.cn511434-20250415-00171

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes, characterized by high blindness rates and a severe impact on patients' quality of life. Despite adequate glycemic control, some patients exhibit persistent progression of retinal microvascular damage, known as the "metabolic memory" phenomenon. Studies have revealed that the essence of this phenomenon is the sustained expression of epigenetic reprogramming induced by metabolic stress, in which abnormal mitochondrial DNA (mtDNA) methylation plays a pivotal role. Metabolic abnormalities such as hyperglycemia, hyperhomocysteinemia, and hyperlipidemia can alter mtDNA methylation patterns, triggering cascading pathological processes including oxidative stress, chronic inflammation, and neurovascular network disorders, remodeling mitochondrial energy metabolism, and promoting the evolution of DR from subclinical compensatory stage to irreversible structural damage. Abnormal mtDNA methylation serves as a hallmark of metabolic memory and a core driver of microvascular lesions, providing an important theoretical basis for in-depth analysis of metabolic memory mechanisms and exploration of DR intervention strategies. Current research needs to further elucidate its role in DR. Future efforts require integration of multi-dimensional epigenetic biomarkers, precise intervention approaches, and clinical translational research to advance the early diagnosis and individualized treatment of DR.

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12. Quan W, Jiao Y, Xue C, et al. The effect of exogenous free N^ε-(carboxymethyl) lysine on diabetic-model goto-kakizaki rats: metabolomics analysis in serum and urine[J]. J Agric Food Chem, 2021, 69(2): 783-793. DOI: 10.1021/acs.jafc.0c06445.
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18. Mohammad G, Kowluru RA. Homocysteine disrupts balance between MMP-9 and its tissue inhibitor in diabetic retinopathy: the role of DNA methylation[J/OL]. Int J Mol Sci, 2020, 21(5): 1771[2020-03-05]. https://pubmed.ncbi.nlm.nih.gov/32150828/. DOI: 10.3390/ijms21051771.
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22. Yang HQ, Martinez-Ortiz W, Hwang J, et al. Palmitoylation of the K_ATP channel Kir6.2 subunit promotes channel opening by regulating PIP₂ sensitivity[J]. Proc Natl Acad Sci USA, 2020, 117(19): 10593-10602. DOI: 10.1073/pnas.1918088117.
23. Long Q, Chen H, Yang W, et al. Delphinidin-3-sambubioside from Hibiscus sabdariffa. L attenuates hyperlipidemia in high fat diet-induced obese rats and oleic acid-induced steatosis in HepG2 cells[J]. Bioengineered, 2021, 12(1): 3837-3849. DOI: 10.1080/21655979.2021.1950259.
24. Cai C, Gu C, He S, et al. TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy[J]. Clin Epigenetics, 2024, 16(1): 6. DOI: 10.1186/s13148-023-01619-1.
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27. Malaviya P, Kowluru RA. Diabetic retinopathy and regulation of mitochondrial glutathione-glutathione peroxidase axis in hyperhomocysteinemia[J/OL]. Antioxidants (Basel), 2024, 13(3): 254[2024-02-20]. https://pubmed.ncbi.nlm.nih.gov/38539790/. DOI: 10.3390/antiox13030254.
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