Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease
Open accessAbstract
Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.
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- Authors
- Cha, M.-Y., Cho, H. J., Kim, C., Jung, Y. O., Kang, M. J., Murray, M. E., Hong, H. S., Choi, Y.-J., Choi, H., Kim, D. K., Choi, H., Kim, J., Dickson, D. W., Song, H. K., Cho, J. W., Yi, E. C., Kim, J., Jin, S. M., & Mook-Jung, I.
- Affiliations
- Seoul National University (KR)
- Mayo Clinic (US)
- Korea University (KR)
- Medifron (South Korea) (KR)
- Yonsei University (KR)
- Corresponding author
- Jin, Seok Min
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-09-10
- Volume
- 24
- Issue
- 22
- Pages
- 6492-6504
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5007609
- OpenAlex
- W1886846543
- Semantic Scholar
- b9c5b1739c36a7181b0eedf2ec31a10f787ba9df
- Cited by
- 95
- References
- 47
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 15 · 2021: 18 · 2020: 10 · 2019: 5 · 2018: 13 · 2017: 8 · 2016: 2 · 2015: 1
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Research Foundation (2015R1A2A1A05001794, 2014M3C7A1046047, 2015M3C7A1028790)
- Medical Research Center (2011-0030738)
- KIST Institutional Program (2E24242-13-135, NRF-2013R1A2A1A01008067, GHR Foundation (JK), NIH, AG016574)
- Jacoby Professorship of Alzheimer Research
- Donors Cure Foundation
- Einstein Aging Study (NIH P01-AG03949)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- O-GlcNAcylation, Alzheimer's disease, mitochondrial ATP synthase, ATP5A, amyloid-beta, O-GlcNAc transferase, protein glycosylation, ATP production, ATPase activity, neurodegeneration, transgenic mouse model
- MeSH terms
- Acetylglucosamine, Adenosine Triphosphate, Alzheimer Disease, Animals, beta-N-Acetylhexosaminidases, Cricetulus, Disease Models, Animal, Glycosylation, HeLa Cells, Humans, Mice, Transgenic, Mitochondria, Oxidative Phosphorylation Coupling Factors, Protein Processing, Post-Translational, CHO Cells, N-Acetylglucosaminyltransferases, Mitochondrial Proton-Translocating ATPases, Mice
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