Parkinson's disease protein DJ-1 regulates ATP synthase protein components to increase neuronal process outgrowth

Cell Death Dis. 2019 Jun 13;10(6):469. doi: 10.1038/s41419-019-1679-x.

Abstract

Familial Parkinson's disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the F1FO ATP synthase β subunit. DJ-1's interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial uncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive loss of neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATP synthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase c-subunit can form an uncoupling channel; we measured, therefore, ATP synthase F1 (β subunit) and c-subunit protein levels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that found in their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit. We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase protein components.

Publication types

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

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism*
  • Gene Expression
  • Humans
  • Membrane Potential, Mitochondrial / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Protein Binding
  • Protein Deglycase DJ-1 / genetics
  • Protein Deglycase DJ-1 / metabolism*
  • Rats, Sprague-Dawley

Substances

  • ATP5F1B protein, human
  • PARK7 protein, human
  • Protein Deglycase DJ-1
  • Mitochondrial Proton-Translocating ATPases