Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease
- Authors
- Cha, Moon-Yong; Cho, Hyun Jin; Kim, Chaeyoung; Jung, Yang Ouk; Kang, Min Jueng; Murray, Melissa E.; Hong, Hyun Seok; Choi, Young-Joo; Choi, Heesun; Kim, Dong Kyu; Choi, Hyunjung; Kim, Jisoo; Dickson, Dennis W.; Song, Hyun Kyu; Cho, Jin Won; Yi, Eugene C.; Kim, Jungsu; Jin, Seok Min; Mook-Jung, Inhee
- Issue Date
- 15-11월-2015
- Publisher
- OXFORD UNIV PRESS
- Citation
- HUMAN MOLECULAR GENETICS, v.24, no.22, pp.6492 - 6504
- Indexed
- SCIE
SCOPUS
- Journal Title
- HUMAN MOLECULAR GENETICS
- Volume
- 24
- Number
- 22
- Start Page
- 6492
- End Page
- 6504
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/91897
- DOI
- 10.1093/hmg/ddv358
- ISSN
- 0964-6906
- Abstract
- Glycosylation with O-linked beta-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-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as A beta-treated cells. Indeed, A beta 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 A beta-induced impairment in ATP production and ATPase activity. These results indicate that A beta-mediated reduction of ATP synthase activity in AD pathology results from direct binding between A beta and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.
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