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- Title
Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.
- Authors
Moon-Yong Cha; Hyun Jin Cho; Chaeyoung Kim; Yang Ouk Jung; Min Jueng Kang; Murray, Melissa E.; Hyun Seok Hong; Young-Joo Choi; Heesun Choi; Dong Kyu Kim; Hyunjung Choi; Jisoo Kim; Dickson, Dennis W.; Hyun Kyu Song; Jin Won Cho; Yi, Eugene C.; Jungsu Kim; Seok Min Jin; Inhee Mook-Jung
- Abstract
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-GlcNAcylationwas decreased in the brains of AD patients and transgenic mouse model, aswell 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
- Publication
Human Molecular Genetics, 2015, Vol 24, Issue 22, p6492
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddv358