New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms

Biochim Biophys Acta. 2010 Mar;1800(3):205-12. doi: 10.1016/j.bbagen.2009.04.019. Epub 2009 May 4.


The Mitchell Theory implies the proton motive force Deltap across the inner mitochondrial membrane as the energy-rich intermediate of oxidative phosphorylation. Deltap is composed mainly of an electrical (DeltaPsi(m)) and a chemical part (DeltapH) and generated by the respiratory chain complexes I, III and IV. It is consumed mostly by the ATP synthase (complex V) to produce ATP. The free energy of electron transport within the proton pumps is sufficient to generate Deltap of about 240 mV. The proton permeability of biological membranes, however, increases exponentially above 130 mV leading to a waste of energy at high values (DeltaPsi(m)>140 mV). In addition, at DeltaPsi(m)>140 mV, the production of the superoxide radical anion O(2)(-) at complexes I, II and III increases exponentially with increasing DeltaPsi(m). O(2)(-) and its neutral product H(2)O(2) (=ROS, reactive oxygen species) induce oxidative stress which participates in aging and in the generation of degenerative diseases. Here we describe a new mechanism which acts independently of the Mitchell Theory and keeps DeltaPsi(m) at low values through feedback inhibition of complex IV (cytochrome c oxidase) at high ATP/ADP ratios, thus preventing the formation of ROS and maintaining high efficiency of oxidative phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • Disease
  • Humans
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Models, Theoretical
  • Oxidative Phosphorylation*
  • Oxidative Stress
  • Oxygen Consumption
  • Protein Kinases / metabolism
  • Protein Subunits / metabolism
  • Proton Pumps
  • Reactive Oxygen Species / metabolism


  • Protein Subunits
  • Proton Pumps
  • Reactive Oxygen Species
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Protein Kinases