2.B.54. The Small Molecule Uncoupling Protonophore (SMUP) Superfamily 

Excessive build-up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability provides a means to counteract this build-up. countermeasure. Holmuhamedov et al. 2004 demonstrated that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitate transmembrane proton translocation, generating H⁺-selective current through planar phospholipid membranes. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained under K⁺-free conditions and shared the characteristics of the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4-dinitrophenol, but not 2,4-dinitrotoluene, lacking protonophoric properties, preserved functional recovery of the ischemic heart. The identified protonophoric property of potassium channel openers suggests a previously unrecognized component in their mechanism of cardioprotection (Holmuhamedov et al. 2004).