Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Thorez pr. 44, 194223 St. Petersburg, Russia.
Int J Mol Sci. 2022 Aug 11;23(16):8964. doi: 10.3390/ijms23168964.
Recent data have shown that the mitochondrial permeability transition pore (MPTP) is the complex of the Ca-modified adenine nucleotide translocase (ANT) and the Ca-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 Ca-loaded rat liver mitochondria. In this study, the effects of thiol-modifying agents (eosin-5-maleimide (EMA), fluorescein isothiocyanate (FITC), Cu(o-phenanthroline) (Cu(OP)), 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) decline, decreases in state 3, 4, and 3U (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)) 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.
最近的数据表明，线粒体通透性转换孔（MPTP）是钙修饰的腺嘌呤核苷酸转位酶（ANT）和钙修饰的 ATP 合酶的复合物。我们在之前的研究中发现，ANT 构象变化可能参与 Tl 诱导的 Ca 负载大鼠肝线粒体内膜 MPTP 开放。在这项研究中，巯基修饰剂（曙红 5-马来酰亚胺（EMA）、异硫氰酸荧光素（FITC）、Cu(o-邻菲咯啉)（Cu(OP)）和 Embelin（Emb））和 MPTP 抑制剂（ADP、环孢菌素 A（CsA）、N-乙基马来酰亚胺（NEM）和三氟拉嗪（TFP））对 MPTP 开放的影响与肿胀增加、膜电位（ΔΨ）下降、状态 3、4 和 3U（2,4-二硝基苯酚去耦）呼吸减少以及内膜游离巯基含量变化同时进行了测试。这些巯基修饰剂对研究线粒体特性的影响是多向的，并且明显依赖于它们的浓度。这项研究表明，Tl 诱导的 Ca 负载线粒体内膜 MPTP 开放可能是由于使用的试剂（EMA、FITC、Emb、Cu(OP))与 ANT、线粒体磷酸盐载体（PiC）和线粒体呼吸链复合物的活性基团相互作用所致。这项研究进一步深入了解了铊毒性的原因，可能有助于开发治疗铊中毒的新方法。
