Chemiosmotic coupling in oxidative phosphorylation: The history of a hard experimental effort hampered by the Heisenberg indeterminacy principle

Understanding how biological systems convert and store energy is a primary goal of biological research. However, despite the formulation of Mitchell’s chemiosmotic theory, which allowed taking fundamental steps forward, we are still far from the complete decryption of basic processes as oxidative phosphorylation (OXPHOS) and photosynthesis. After more than half a century, the chemiosmotic theory appears to need updating, as some of its assumptions have proven incorrect in the light of the latest structural data on respiratory chain complexes, bacteriorhodopsin and proton pumps. Moreover, the existence of an OXPHOS on the plasma membrane of cells casts doubt on the possibility to build up a transversal proton gradient across it, while paving the way for important applications in the field of neurochemistry and oncology. Up-to date biotechnologies, such as fluorescence indicators can follow proton displacement and sinks, and a number of reports have elegantly demonstrated that proton translocation is lateral rather than transversal with respect to the coupling membrane. Furthermore, the definition of the physical species involved in the transfer (proton, hydroxonium ion or proton currents) is still unresolved even though the latest acquisitions support the idea that protonic currents, difficult to measure, are involved. It seems that the concept of diffusion of the proton expressed more than two centuries ago by Theodor von Grotthuss, is decisive for overcoming these issues. All these uncertainties remember us that also in biology it is necessary to take into account the Heisenberg indeterminacy principle, that sets limits to analytical questions.