Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease

Moon Yong Cha, Hyun Jin Cho, Chaeyoung Kim, Yang Ouk Jung, Min Jueng Kang, Melissa E. Murray, Hyun Seok Hong, Young Joo Choi, Heesun Choi, Dong Kyu Kim, Hyunjung Choi, Jisoo Kim, Dennis W. Dickson, Hyun Kyu Song, Jin Won Cho, Eugene C. Yi, Jungsu Kim, Seok Min Jin, Inhee Mook-Jung

Research output: Contribution to journalArticle

30 Citations (Scopus)

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 a (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 decreasedATP 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.

Original languageEnglish
Pages (from-to)6492-6504
Number of pages13
JournalHuman Molecular Genetics
Volume24
Issue number22
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    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. (2015). Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease. Human Molecular Genetics, 24(22), 6492-6504. https://doi.org/10.1093/hmg/ddv358