Weak C–H acids as protonophores can carry hydrogen ions through lipid membranes and mitochondria: a case of o-carborane

Abstract

ortho-Carborane (1,2-C2B10H12) was found to be a carrier of protons in both mitochondrial and artificial lipid membranes, suggesting that this dicarborane can reversibly release hydrogen ions and diffuse through the membranes in neutral and anionic forms. Similar to conventional uncouplers (e.g. 2,4-dinitrophenol), o-carborane stimulated mitochondrial respiration and decreased the membrane potential at concentrations of tens of micromoles. Protonophoric activity of o-carborane was observed both by a fluorometric assay using pyranine-loaded liposomes and electrical current measurements across planar lipid bilayers. Substantial contribution of the proton flux to the o-carborane-mediated current was proved by a shift of the zero current voltage upon imposing a pH gradient across the membrane. Meta-carborane (1,7-C2B10H12) lacked the protonophoric activity in line with its reduced C-H acidity. The results suggest that weak C-H acids can exhibit protonophoric activity in the biological environment. The finding of a new class of protonophoric compounds is of substantial interest due to promising anti-obesity and anti-diabetic properties of uncouplers.

Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases

“…Finally, weak C-H acids, such as ortho-carborane (1,2-C 2 B 10 H 12 ), were also shown to have global uncoupling properties, when used at concentrations comparable to FCCP (10 μM range) [82]. N -acyl amino acids also exhibit such properties, and a hydrolysis-resistant N-acyl amino acid analogue was recently identified.…”

6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

“…Given the broad definition of a protonophore and the lack of a defined biological target, the chemical space is quite vast. As shown in Figure , phenols (e.g., DNP), dicyanohydrazones (e.g., FCCP), arylamides (e.g., niclosamide and nitazoxanide), triazoles (e.g., OPC-163493), perfluoroalkyl­sulfonamides, benzimidazoles, , and carboranes , are among the diverse class of protonophores studied. Recently, through a high throughput screen, we reported a novel chemical scaffold in BAM15 ( 8 ), which elicits selective depolarization of the mitochondrial inner membrane. , The mitochondrial-specificity of 8 is a unique departure from other protonophores and offers a potential breakthrough to overcome the toxicity of protonophores.…”