Adenine nucleotide-dependent inhibition of permeability transition pore: adenine nucleotide translocase and other players.

Authors

Alexey G Kruglov, Anna B Nikiforova, Marina V Akulenko, Ekaterina S Kharechkina, Irina V Odinokova, Ekhson L Holmuhamedov

Published in

Biochimica et biophysica acta. Bioenergetics. Pages 149604. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Changes in the level and the ratio of adenine nucleotides (AN) are a common consequence of ischemia, which can promote mitochondrial permeability transition pore (mPTP) opening and cell death upon reperfusion. However, the mechanism of AN-dependent mPTP inhibition is not entirely clear. Here we studied the effects of inorganic phosphate, Mg²⁺, as well as the inhibitors of adenylate translocase (ANT) and FoF₁-ATP synthase (F-ATPase) on the AN-dependent mPTP suppression and AN turnover mediated by a short Ca²⁺-dependent mitochondrial carrier (SCaMC). Also, we indirectly assessed the contribution of Ca²⁺ buffering by AN to mPTP suppression. We found that, at near-physiologic concentrations, AN suppressed mPTP opening (swelling) and increased the Ca²⁺-retention capacity much stronger than the ANT inhibitor bongkrekic acid (BA). Inorganic phosphate (Pi) and Mg²⁺ modulated the protective effect of AN. In solution, AN were an incomparably weaker Ca²⁺ buffer than matrix Pi. AN preserved the capability to suppress mPTP opening in the presence of both BA and carboxyatractyloside (CATR). The sensitivity of AN-dependent mPTP suppression to CATR decreased with a decrease in the Pi level. Mg²⁺ and BA, in contrast to CATR, partially inhibited the SCaMC-mediated AN turnover. The analysis of these and the earlier obtained data allowed us to propose a new mechanism of AN-dependent mPTP suppression: the coordinated ANT- and SCaMC-mediated AN turnover, which fine-tunes the Pi, Ca²⁺, and H⁺ ratios in the matrix for efficient Ca²⁺ sequestration. The mechanism does not require ANT stabilization in any conformation, allosteric regulators, and the formation of AN-Ca²⁺-Pi complexes.

PMID:
42628868
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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