Hypothesis of lipid-phase-continuity proton transfer for aerobic ATP synthesis

J Cereb Blood Flow Metab. 2013 Dec;33(12):1838-42. doi: 10.1038/jcbfm.2013.175. Epub 2013 Oct 2.


The basic processes harvesting chemical energy for life are driven by proton (H(+)) movements. These are accomplished by the mitochondrial redox complex V, integral membrane supramolecular aggregates, whose structure has recently been described by advanced studies. These did not identify classical aqueous pores. It was proposed that H(+) transfer for oxidative phosphorylation (OXPHOS) does not occur between aqueous sources and sinks, where an energy barrier would be insurmountable. This suggests a novel hypothesis for the proton transfer. A lipid-phase-continuity H(+) transfer is proposed in which H(+) are always bound to phospholipid heads and cardiolipin, according to Mitchell's hypothesis of asymmetric vectorial H(+) diffusion. A phase separation is proposed among the proton flow, following an intramembrane pathway, and the ATP synthesis, occurring in the aqueous phase. This view reminiscent of Grotthus mechanism would better account for the distance among the Fo and F1 moieties of FoF1-ATP synthase, for its mechanical coupling, as well as the necessity of a lipid membrane. A unique active role for lipids in the evolution of life can be envisaged. Interestingly, this view would also be consistent with the evidence of an OXPHOS outside mitochondria also found in non-vesicular membranes, housing the redox complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cardiolipins / metabolism
  • Humans
  • Membrane Lipids / metabolism*
  • Oxidative Phosphorylation
  • Proton-Translocating ATPases / metabolism*
  • Protons


  • Cardiolipins
  • Membrane Lipids
  • Protons
  • Adenosine Triphosphate
  • Proton-Translocating ATPases