An assessment of the chemiosmotic hypothesis of mitochondrial energy transduction.

It is argued that a proton concentration difference and/or a membrane potential is not the form into which the free energy of the oxidation-reduction reactions of the mitochondrial respiratory chain is first transduced. It is suggested that the search for a chemical intermediate should be continued in spite of the conclusion by some investigators that the chemical hypothesis is untenable. It is asked whether pH changes when measured in solutions containing mitochondria can be interpreted as evidence for H+ movements, also, whether there is a continuous, renewable and stable electrochemical proton concentration difference (delta mu H+) across the mitochondrial membrane, and whether in fact the delta mu H+ is a necessary intermediate in the synthesis of ATP. The four postulates of Mitchell's chemiosmotic hypothesis of energy transduction are discussed point by point. It is agreed that "The systems are plugged through a topologically closed insulating membrane," which probably is not "a nonaqueous osmotic barrier," and which probably does not have an unusually "low permeability to solutes and to H+ and OH- in particular" when compared with other membranes. There is disagreement with the statement that "Respiratory and photoredox systems are chemiosmotic membrane-located protonmotive chains" in that it is suggested by others that chemiosmosis is chemically nonexistent and that thermodynamically it would lack control. The subsequent statement, "having a characteristic----H+/2 epsilon- stoichiometry," is rendered uncertain by the experimental findings of values greater than 2H+/2 epsilon-/site and probably as large as 4H+/2 epsilon-/site. The proposal that "The synthetase is a chemiosmotic membrane-located reversible motive ATPase" requires the assumption that the ATP synthetase is the same enzyme as the ATPase, but functioning in the reverse direction. It is considered possible that there are two enzymes in the multi-subunit ATPase complex: one the hydrolase, and the other the synthetase. The further proposal, "having characteristic----H+/P stoichiometry" requires that the ratio be 2 according to Mitchell. However, values of 3, as well as larger values, have been reported by others, which introduces a large element of uncertainty. There is no disagreement with the statement that "There are proton-linked (or hydroxyl ion-linked) solute porter systems for osmotic stabilization and metabolite transport." In fact, this may be the principal reason for having proton efflux or "proton-pumping.''(ABSTRACT TRUNCATED AT 400 WORDS)