REVIEW: Classification of Mitochondrial Protonophoric Uncouplers and their Modifications in Biological Environment

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Yuri N. Antonenko^1,a*, Elena A. Kotova¹, Vladimir S. Krasnov^1,2, and Roman S. Kirsanov¹

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

²Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received: July 14, 2025; Revised: October 7, 2025; Accepted: October 8, 2025

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In this review, we analyze diversity of mitochondrial uncouplers, a class of compounds, which was in the focus of Vladimir Skulachev’s attention throughout his scientific career, starting from the basics of bioenergetics and validation of Mitchell’s chemiosmotic theory to the development of concepts of mild uncoupling and its therapeutic role. The review is the first to put forward the idea of classifying uncouplers by the type of a functional group that provides their protonophoric activity, i.e., the ability to transfer protons across the membrane, causing its depolarization and thereby uncoupling the ATP synthesis from the operation of proton pumps in the electron transport chain. In particular, it is shown that anionic and zwitterionic uncouplers can be divided into groups of OH-, NH-, SH-, and CH-acids. Of importance, here we consider metabolic transformations of mitochondrial uncouplers determining tissue-specificity of their action.

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KEY WORDS: mitochondria, uncouplers, protonophores, oxidative phosphorylation, lipid membranes

DOI: 10.1134/S000629792560245X

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