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Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic
Zaoxia Guo1, Xinnan Li2, Xi Chen1
1Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi, China.
Purpose:
Cataract is a major cause of blindness among patients with diabetes mellitus. The pathology underlying diabetic cataract (DC) is complex because of changes in biological processes caused by chronic hyperglycemia. O-GlcNAcylation is highly dependent on glucose availability and regulates mitochondrial functions. Dysregulation of O-GlcNAcylation has been reported in DC. Mitochondria in lens epithelial cells are key organelles for energy supply and redox homeostasis of the lens. Mitochondrial dysfunction is a hallmark of DC. However, whether O-GlcNAcylation regulates mitochondrial function underlying DC has not been fully studied.
Methods:
An animal model of DC was established in Sprague-Dawley male rats by feeding a 60% high-fat diet and injecting streptozotocin. Mitochondria were visualized using confocal laser scanning microscope and transmission electron microscope. O-GlcNAcylated proteins were verified using liquid chromatography tandem mass spectrometry and immunoprecipitation assays. Lentivirus-encapsulated plasmids were constructed to generate stable transfected cell lines. The histomorphology of the lens was assessed by hematoxylin and eosin staining.
Results:
High glucose levels promoted mitochondrial fission by upregulating Senp1 O-GlcNAcylation at the S137 site. Senp1 S137 O-GlcNAcylation inhibited Fis1 deSUMO1-ylation. Fis1 SUMO1-ylation decreased its interaction with Mfn2, which reduced the contact between mitochondria-associated ER membranes (MAMs), thereby promoting mitochondrial fragmentation. Site-specific mutation of Senp1 S137A released the inhibitory effect on Fis1 deSUMOylation and mitigated high-glucose induced mitochondrial fragmentation.
Conclusions:
Senp1 S137 O-GlcNAcylation regulates mitochondrial fragmentation in lens epithelial cells underlying DC. Senp1 O-GlcNAcylation increase mediates mitochondrial fragmentation by upregulating Fis1 SUMO1-ylation, which in turn reduces the contact of mitochondria-associated endoplasmic reticulum membranes and promotes mitochondrial fragmentation.
