2.B.129.  The Small Molecule Mitochondrial Uncoupler (SMMU) Functional Superfamily 

Mitochondrial uncoupling caused by a wide variety of protonophores (specified below) is differently sensitive to carboxyatractyloside in rat heart and liver mitochondria (Khailova et al. 2024).  Mitochondrial uncoupling by small-molecule protonophores proceeds via transmembrane proton shuttling. The idea of facilitating this process by the adenine nucleotide translocase ANT originated primarily from the partial reversal of the DNP-induced mitochondrial uncoupling by the ANT inhibitor carboxyatractyloside (CATR). The sensitivity to CATR was also observed for the action of such potent OxPhos uncouplers as BAM15, SF6847, FCCP and niclosamide. Khailova et al. 2024 reported measurements of the CATR effect on the activity of a large number of conventional and novel uncouplers in isolated mammalian (rat) mitochondria. Despite the broad variety of chemical structures, CATR attenuated the uncoupling efficacy of all the anionic protonophores in rat heart mitochondria with high abundance of ANT, whereas the effect was much less pronounced or even absent, e.g. for SF6847, in rat liver mitochondria with low ANT content. The fact that the uncoupling action is tissue specific for a broad spectrum of anionic protonophores is highlighted. Only with the cationic uncoupler ellipticine and the channel-forming peptide gramicidin A, no sensitivity to CATR was found even in rat heart mitochondria. By contrast, with the recently described ester-stabilized ylidic protonophores (Khailova et al. 2023), the stimulating effect of CATR was observed both in liver and heart mitochondria.

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