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

• Published in: Human molecular genetics Vol. 24; no. 22; pp. 6492 - 6504
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.11.2015
• Subjects: Acetylglucosamine - metabolism; Adenosine Triphosphate - metabolism; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; beta-N-Acetylhexosaminidases - metabolism; CHO Cells; Cricetulus; Disease Models, Animal; Glycosylation; HeLa Cells; Humans; Mice; Mice, Transgenic; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; N-Acetylglucosaminyltransferases - metabolism; Oxidative Phosphorylation Coupling Factors - genetics; Oxidative Phosphorylation Coupling Factors - metabolism; Protein Processing, Post-Translational
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv358

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.