Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada C1A 4P3.
Toxicol In Vitro. 2012 Feb;26(1):164-73. doi: 10.1016/j.tiv.2011.10.017. Epub 2011 Nov 6.
Molecular features of cadmium (Cd) and calcium (Ca) uptake and toxicity in rainbow trout liver mitochondria were studied using modulators of mitochondrial permeability transition pore (MPTP), mitochondrial calcium uniporter (MCU) and rapid uptake mode (RaM). Malate-glutamate energized mitochondria were exposed to 20μM Cd and 50μM Ca, singly and in combination, with and without addition of ruthenium red (RR), cyclosporin A (CsA), bongkrekic acid (BKA) or dithiothreitol (DTT). State 3 mitochondrial respiration was inhibited by 50% by either Cd or Ca, and by 70% when the two cations were added simultaneously. All the modulators tested reduced the inhibition of state 3 respiration with DTT completely reversing the Cd effect. While state 4 respiration was unaffected by Ca and/or Cd, 1.5-3 fold stimulation was observed on addition of the modulators. Uncoupler-stimulated respiration was inhibited by Cd, Ca and Cd+Ca with complete (DTT) and partial (RR, CsA, BKA) protection of the Cd and Cd+Ca effects. All the modulators completely reversed the Ca-induced inhibition. Swelling, the hallmark of MPTP, measured following incubation of mitochondria with 0-100μM of the two cations, singly and in combination, was abolished by all the modulators. Overall these data show the existence of membrane channels in rainbow trout liver mitochondria with some characteristics similar to mammalian MPTP, MCU and RaM. Moreover, entry of Ca and Cd into mitochondria is important in the toxicity of these cations.
采用线粒体通透性转换孔（MPTP）、线粒体钙单向转运体（MCU）和快速摄取模式（RaM）调节剂，研究了镉（Cd）和钙（Ca）在虹鳟鱼肝线粒体中的摄取和毒性的分子特征。用苹果酸-谷氨酸供能的线粒体，分别或同时暴露于 20μM Cd 和 50μM Ca 中，并添加或不添加钌红（RR）、环孢菌素 A（CsA）、棒曲霉素（BKA）或二硫苏糖醇（DTT）。结果显示，Cd 或 Ca 将线粒体呼吸状态 3 抑制了 50%，当两种阳离子同时加入时，抑制了 70%。测试的所有调节剂都减少了 DTT 对状态 3 呼吸的抑制作用，完全逆转了 Cd 的作用。尽管 Ca 和/或 Cd 对状态 4 呼吸没有影响，但添加调节剂后观察到 1.5-3 倍的刺激作用。解偶联剂刺激的呼吸被 Cd、Ca 和 Cd+Ca 抑制，DTT 完全保护 Cd 和 Cd+Ca 的作用，RR、CsA 和 BKA 部分保护。所有调节剂完全逆转了 Ca 诱导的抑制作用。在单独或联合使用两种阳离子（0-100μM）孵育线粒体后，测量到作为 MPTP 标志的肿胀被所有调节剂消除。总之，这些数据表明，虹鳟鱼肝线粒体中存在具有某些类似于哺乳动物 MPTP、MCU 和 RaM 特征的膜通道。此外，Ca 和 Cd 进入线粒体在这些阳离子的毒性中很重要。
