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O-GlcNAc impacts mitophagy via the PINK1-dependent pathway
Ibtihal M Alghusen1, Marisa S Carman1, Heather M Wilkins1,2,3
1School of Medicine, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States.
Frontiers in Aging Neuroscience
|August 23, 2024
Summary
Dysfunctional mitochondria accumulate in Alzheimer's disease (AD). This study shows that O-GlcNAc modification is crucial for mitophagy, a process impaired in AD, highlighting a potential therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction and accumulation of damaged mitochondria are early hallmarks of Alzheimer's disease (AD).
- Impaired mitochondrial turnover in AD leads to increased reactive oxygen species, reduced ATP, cellular toxicity, and neurodegeneration.
- Alzheimer's disease is characterized by disruptions in O-GlcNAc (β-N-acetylglucosamine) modification, a key regulatory process in cellular metabolism and protein function.
Purpose of the Study:
- To investigate the role of O-GlcNAc modification in regulating mitophagy, the selective autophagy of damaged mitochondria.
- To examine the impact of modulating O-GlcNAc levels on mitophagy pathways in cellular and animal models of AD.
Main Methods:
- Utilized patient-derived induced pluripotent stem cells, a transgenic AD mouse model, and SH-SY5Y neuroblastoma cell lines.
- Employed biochemical analyses to assess mitophagy.
- Investigated the effects of O-GlcNAcase inhibition (Thiamet-G) and OGT deficiency on mitophagy markers.
Main Results:
- O-GlcNAc plays a critical role in activating mitophagy; stimulating mitophagy decreases cellular O-GlcNAc and increases mitochondrial O-GlcNAc.
- Inhibition of O-GlcNAcase (OGA) with Thiamet-G (TMG) increased mitochondrial levels of mitophagy proteins PINK1 and LC3, with evidence of increased O-GlcNAc on PINK1.
- Conversely, reducing O-GlcNAc levels via OGT knockdown decreased PINK1 and LC3 expression, and mitochondria from OGT-deficient mice showed reduced PINK1 and LC3.
Conclusions:
- O-GlcNAc is essential for the activation and progression of mitophagy.
- The O-GlcNAc-mediated regulation of mitophagy is disrupted in Alzheimer's disease, suggesting a novel mechanism underlying AD pathogenesis.
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