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O-GlcNAcylation Suppressed Apoptosis and Ferroptosis in Traumatic Brain Injury by Enhancing Mitophagy
Li Zhang1, Maoxin Fei1, Yaonan Peng1
1Department of Neurosurgery, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, P.R. China.
Abstract:
O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a distinctive post-translational modification (PTM), is ubiquitously present in numerous nuclear and mitochondrial proteins. The emerging role of O-GlcNAcylation is increasingly recognized for its involvement in various diseases. However, its role in traumatic brain injury (TBI) has not been explored. This study was aimed to explore the neuroprotection of O-GlcNAcylation in both in vivo and in vitro TBI models. Our results revealed that the levels of O-GlcNAcylation were increased after TBI. Up-regulation of O-GlcNAcylation by Thiamet G (TMG) provided neuroprotection after TBI. Moreover, TMG inhibited TBI-triggered blood-brain barrier (BBB) damage. Furthermore, TMG alleviated apoptosis and ferroptosis caused by TBI. Besides, TMG activated mitophagy after TBI, and the neuroprotection of TMG was attenuated when mitophagy was inhibited. Importantly, TMG also attenuated cell death, decreased apoptosis and ferroptosis, and activated mitophagy after TBI in vitro. Taken together, our data provided the first evidence that O-GlcNAcylation played a crucial role in TBI by activation of mitophagy.
Insights
O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is elevated after traumatic brain injury (TBI). Enhancing O-GlcNAcylation with Thiamet G protects against TBI by activating mitophagy and reducing cell death.
Area of Science:
- Biochemistry
- Neuroscience
- Cell Biology
Background:
- O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is a crucial post-translational modification found in nuclear and mitochondrial proteins.
- O-GlcNAcylation's role in various diseases is recognized, but its impact on traumatic brain injury (TBI) remains unexplored.
Purpose of the Study:
- To investigate the neuroprotective effects of O-GlcNAcylation in TBI.
- To explore the underlying mechanisms, including mitophagy, in TBI models.
Main Methods:
- Utilized in vivo and in vitro TBI models.
- Administered Thiamet G (TMG) to up-regulate O-GlcNAcylation.
- Assessed TBI-induced damage, apoptosis, ferroptosis, and mitophagy.
Main Results:
- O-GlcNAcylation levels increased post-TBI.
- TMG treatment provided neuroprotection, reduced blood-brain barrier damage, and alleviated apoptosis and ferroptosis.
- TMG activated mitophagy, and inhibiting mitophagy attenuated TMG's neuroprotective effects.
Conclusions:
- O-GlcNAcylation plays a significant role in TBI pathogenesis.
- Up-regulating O-GlcNAcylation via TMG demonstrates neuroprotective potential.
- Mitophagy activation is a key mechanism underlying O-GlcNAcylation's neuroprotection in TBI.
