Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic...

Area of Science:

• Ophthalmology
• Cell Biology
• Biochemistry

Background:

• Diabetic cataract (DC) is a leading cause of blindness in diabetes mellitus patients.
• Chronic hyperglycemia in diabetes disrupts cellular processes, including mitochondrial function, contributing to DC pathology.
• O-GlcNAcylation, a glucose-dependent modification, regulates mitochondrial functions, but its specific role in DC remains understudied.

Purpose of the Study:

• To investigate the role of O-GlcNAcylation in regulating mitochondrial function in the context of diabetic cataract.
• To elucidate the molecular mechanisms by which O-GlcNAcylation influences mitochondrial dynamics in lens epithelial cells.

Main Methods:

• Established a rat model of diabetic cataract using high-fat diet and streptozotocin.
• Utilized confocal and transmission electron microscopy to visualize mitochondrial morphology.
• Employed liquid chromatography-tandem mass spectrometry and immunoprecipitation to identify O-GlcNAcylated proteins.
• Generated stable cell lines using lentivirus vectors for functional studies.

Main Results:

• High glucose levels induced mitochondrial fission by upregulating Senp1 O-GlcNAcylation at the S137 site.
• Senp1 S137 O-GlcNAcylation inhibited Fis1 deSUMOylation, leading to decreased interaction with Mfn2.
• This disruption reduced contact between mitochondria-associated ER membranes (MAMs), promoting mitochondrial fragmentation.
• Mutating Senp1 at S137 to alanine (S137A) mitigated high-glucose-induced mitochondrial fragmentation.

Conclusions:

• Senp1 O-GlcNAcylation at the S137 site is a key regulator of mitochondrial fragmentation in diabetic cataract.
• Increased Senp1 O-GlcNAcylation promotes mitochondrial fragmentation by upregulating Fis1 SUMOylation, disrupting MAMs.
• Targeting Senp1 O-GlcNAcylation may offer a therapeutic strategy for diabetic cataract.