Classification of Mitochondrial Protonophoric Uncouplers and Their Modifications in Biological Environment

This review is devoted to an analysis of the diversity of mitochondrial uncouplers, a class of compounds that Vladimir Petrovich Skulachev paid primary attention to throughout his scientific career, from the foundations of bioenergetics and the proof of the validity of Mitchell's chemiosmotic theory to the development of the concept of mild uncoupling and its therapeutic role. The review puts forward for the first time the idea of classifying uncouplers according to the type of functional group that provides their protonophoric activity, i.e., the ability to transfer protons across the membrane, causing its depolarization and thus uncoupling the work of proton pumps in the electron transport chain and ATP synthesis. In particular, it is shown that anionic and zwitterionic uncouplers can be divided into groups of OH-, NH-, SH- and CH-acids. An important aspect of this review is the consideration of metabolic transformations of mitochondrial uncouplers that determine the tissue specificity of their action.