ArticleFrontiers in aging neuroscience2024
O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.
Article in Frontiers in aging neuroscience, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration.Neural regeneration research · 2026Article
- Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.Brain sciences · 2026Review
- Review
- cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives.Journal of neuroinflammation · 2025Review
- O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review).Molecular medicine reports · 2025Review
- Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.Journal of Alzheimer's disease : JAD · 2025Article
- Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.Neurochemical research · 2025Review
- OGA promotes human dental pulp stem cell senescence and inhibits mitophagy by inhibition of O-GlcNAcylation of KLF2.BMC oral health · 2025Article
- O-linked β-N-acetylglucosamine modification in diabetic foot ulcer pathogenesis.Burns & trauma · 2025Review
- Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.International journal of biological sciences · 2025Article
- Review
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Authors and funding
12 authors.
Funding
Abstract
Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively. Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses. Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression. Conclusion: Collectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.
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