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

Hum Mol Genet. 2015 Nov 15;24(22):6492-504. doi: 10.1093/hmg/ddv358. Epub 2015 Sep 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism
  • Adenosine Triphosphate / metabolism
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Animals
  • 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
  • beta-N-Acetylhexosaminidases / metabolism


  • Oxidative Phosphorylation Coupling Factors
  • Adenosine Triphosphate
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • F(6) ATPase
  • Mitochondrial Proton-Translocating ATPases
  • Acetylglucosamine