Mitchell’s hypothesis

The chemiosmotic hypothesis had the great virtue of predicting the following consequences which could be tested (1) electron-transport driven proton pumps with defined stoichiometries and (2) a separate ATP synthase, which could be driven by a pH gradient or membrane potential. Mitchell s hypothesis was initially greeted with skepticism but it encouraged many people, including Mitchell and his associate Jennifer Moyle, to test these predictions, which were soon found to be correct.178... 

The chemiosmotic coupling hypothesis, proposed by P. Mitchell, is the most attractive explanation, and many experimental observations now support this idea. Simply stated, Mitchell s hypothesis suggests that electron transfer is accompanied by transport of protons across the membrane. 

Figure 1. Chemiosmotic coupling in oxidative phosphorylation. The model is drawn according to Mitchell s hypothesis for mitochondria, but might also apply to other systems of phosphorylation.

What proved a triumph for Mitchell s hypothesis was the experiments involving simultaneous insertion of ATP synthtases and of one of the primary pumps.163 The synthesis of ATP was accomplished on liposomes. Addition of substances increasing the conductance of the membrane disturbed the coupling both in liposomes and in mitochondria. 

I admit that when I first read his proposition, I was not impressed. In 1965 I published a book on Mechanisms in Bioenergetics and did not even mention the chemiosmotic hypothesis. Phil Handler who wrote a generous review of my book in Science objected to my failure to discuss Mitchell s hypothesis. By the time his review appeared I knew that his criticism was justified because Peter Mitchell had visited me in New York in 1965. This was another important event in my scientific life. Not that I really understood most of what Mitchell said during these days of intensive discussions, but I opened my mind to a new way of thinking. I am now convinced that the basic formulations of his chemiosmotic hypothesis are correct, namely that the function of the respiratory chain is to translocate protons and that the return of those protons via the oligomycin-sensitive ATPase is responsible for ATP formation. Thus the problem of the mecham sm of coupling of oxidation and phosphorylation is basically solved. 

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