The Joint Influence of Tl⁺ and Thiol-Modifying Agents on Rat Liver Mitochondrial Parameters In Vitro

Recent data have shown that the mitochondrial permeability transition pore (MPTP) is the complex of the Ca²⁺-modified adenine nucleotide translocase (ANT) and the Ca²⁺-modified ATP synthase. We found in a previous study that ANT conformational changes may be involved in Tl⁺-induced MPTP opening in the inner membrane of Ca²⁺-loaded rat liver mitochondria. In this study, the effects of thiol-modifying agents (eosin-5-maleimide (EMA), fluorescein isothiocyanate (FITC), Cu(o-phenanthroline)₂ (Cu(OP)₂), and embelin (Emb)), and MPTP inhibitors (ADP, cyclosporine A (CsA), n-ethylmaleimide (NEM), and trifluoperazine (TFP)) on MPTP opening were tested simultaneously with increases in swelling, membrane potential (ΔΨ_mito) decline, decreases in state 3, 4, and 3U_DNP (2,4-dinitrophenol-uncoupled) respiration, and changes in the inner membrane free thiol group content. The effects of these thiol-modifying agents on the studied mitochondrial characteristics were multidirectional and showed a clear dependence on their concentration. This research suggests that Tl⁺-induced MPTP opening in the inner membrane of calcium-loaded mitochondria may be caused by the interaction of used reagents (EMA, FITC, Emb, Cu(OP)₂) with active groups of ANT, the mitochondrial phosphate carrier (PiC) and the mitochondrial respiratory chain complexes. This study provides further insight into the causes of thallium toxicity and may be useful in the development of new treatments for thallium poisoning.