Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease

Nat Commun. 2016 May 6;7:11483. doi: 10.1038/ncomms11483.

Abstract

F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer's disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Adenosine Triphosphate / metabolism*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism*
  • Carrier Proteins / metabolism*
  • Disease Progression
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Neurons / metabolism*
  • Oxidative Phosphorylation
  • Oxidative Stress

Substances

  • Amyloid beta-Peptides
  • Carrier Proteins
  • Membrane Proteins
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases
  • oligomycin sensitivity-conferring protein