Human F1F0 ATP synthase, mitochondrial ultrastructure and OXPHOS impairment: a (super-)complex matter?

PLoS One. 2013 Oct 2;8(10):e75429. doi: 10.1371/journal.pone.0075429. eCollection 2013.

Abstract

Mitochondrial morphogenesis is a key process of cell physiology. It is essential for the proper function of this double membrane-delimited organelle, as it ensures the packing of the inner membrane in a very ordered pattern called cristae. In yeast, the mitochondrial ATP synthase is able to form dimers that can assemble into oligomers. Two subunits (e and g) are involved in this supramolecular organization. Deletion of the genes encoding these subunits has no effect on the ATP synthase monomer assembly or activity and only affects its dimerization and oligomerization. Concomitantly, the absence of subunits e and g and thus, of ATP synthase supercomplexes, promotes the modification of mitochondrial ultrastructure suggesting that ATP synthase oligomerization is involved in cristae morphogenesis. We report here that in mammalian cells in culture, the shRNA-mediated down-regulation of subunits e and g affects the stability of ATP synthase and results in a 50% decrease of the available functional enzyme. Comparable to what was shown in yeast, when subunits e and g expression are repressed, ATP synthase dimers and oligomers are less abundant when assayed by native electrophoresis. Unexpectedly, mammalian ATP synthase dimerization/oligomerization impairment has functional consequences on the respiratory chain leading to a decrease in OXPHOS activity. Finally these structural and functional alterations of the ATP synthase have a strong impact on the organelle itself leading to the fission of the mitochondrial network and the disorganization of mitochondrial ultrastructure. Unlike what was shown in yeast, the impairment of the ATP synthase oligomerization process drastically affects mitochondrial ATP production. Thus we propose that mutations or deletions of genes encoding subunits e and g may have physiopathological implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitochondria / ultrastructure*
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Molecular Sequence Data
  • Oxidative Phosphorylation*
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Sequence Deletion
  • Sequence Homology, Amino Acid

Substances

  • Protein Subunits
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases

Grant support

This work was supported by Centre National de la Recherche Scientifique (CNRS); Université Bordeaux Segalen; Ministère de la recherche et de l′éducation nationale; Région Aquitaine Limousin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.