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

作者：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

来源：Human Molecular Genetics, 2015, 24(22): 6492-6504.

DOI：10.1093/hmg/ddv358

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.

• 出版日期2015-11-15