title: Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.
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-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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Moon-Yong
authors.initials: MY
authors.lastname: Cha
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Yang Ouk
authors.initials: YO
authors.lastname: Jung
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, School of Medicine and School of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Min Jueng
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Medifron-DBT, Inc., Gyeonggi-do, Korea.
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hong
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Life Sciences, Korea University, Seoul, Korea.
authors.forename: Hyun Kyu
authors.initials: HK
authors.lastname: Song
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seodaemun-gu, Seoul, Korea and.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Cho
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, School of Medicine and School of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Yi
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea, inhee@snu.ac.kr neurocom@snu.ac.kr.
authors.forename: Seok Min
authors.initials: SM
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea, inhee@snu.ac.kr neurocom@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010086:Oxidative Phosphorylation Coupling Factors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D010086:Oxidative Phosphorylation Coupling Factors; D000255:Adenosine Triphosphate; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases; D000117:Acetylglucosamine