A comparison of Zn2+- and Ca2+-triggered depolarization of liver mitochondria reveals no evidence of Zn2+-induced permeability transition.
A comparison of Zn2+- and Ca2+-triggered depolarization of liver mitochondria reveals no evidence of Zn2+-induced permeability transition.
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DOI：
10.1016/j.ceca.2009.03.002
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发表时间：
2009-05
期刊：
影响因子：
4
通讯作者：
Dineley KE
中科院分区：
文献类型：
--
作者：
Devinney MJ;Malaiyandi LM;Vergun O;DeFranco DB;Hastings TG;Dineley KE
细胞内Zn 2+毒性与线粒体功能障碍有关。在使用分离的细胞器以及培养的细胞的测定中，Zn 2+使线粒体去极化。有报道认为Zn ~（2+）诱导的去极化是由于线粒体通透性转换孔（mPTP）开放所致。为了更详细地分析这种关系，我们比较了Zn 2+诱导的去极化与钙离子的影响，在单离大鼠肝线粒体电位探针罗丹明123监测。与以前的工作一致，我们发现相对低水平的Ca 2+引起线粒体膜电位的快速，完全和不可逆的损失，这种作用被mPT的经典抑制剂，包括高Mg 2+，ADP和环孢素A减弱。Zn 2+也使线粒体去极化，但仅在相对高的浓度下。此外，Zn 2+诱导的去极化是缓慢的，部分的，有时是可逆的，并且不受mPT抑制剂的影响。我们还比较了钙黄绿素保留试验中Ca 2+和Zn 2+的影响。与文献充分证明的Ca 2+诱导mPT的能力一致，我们发现它引起基质钙黄绿素的快速和大量损失。与此相反，钙黄绿素仍然在锌+处理的线粒体。综合考虑，我们的研究结果表明，Ca 2+和Zn 2+通过相当不同的机制使线粒体去极化，开放的mPTP不是Zn 2+诱导的去极化的直接后果，并且Zn 2+不是特别有效的线粒体抑制剂。
Intracellular Zn2+ toxicity is associated with mitochondrial dysfunction. Zn2+ depolarizes mitochondria in assays using isolated organelles as well as cultured cells. Some reports suggest that Zn2+-induced depolarization results from the opening of the mitochondrial permeability transition pore (mPTP). For a more detailed analysis of this relationship, we compared Zn2+-induced depolarization with the effects of Ca2+ in single isolated rat liver mitochondria monitored with the potentiometric probe Rhodamine123. Consistent with previous work, we found that relatively low levels of Ca2+ caused rapid, complete and irreversible loss of mitochondrial membrane potential, an effect that was diminished by classic inhibitors of mPT, including high Mg2+, ADP and cyclosporine A. Zn2+ also depolarized mitochondria, but only at relatively high concentrations. Furthermore Zn2+-induced depolarization was slower, partial and sometimes reversible, and was not affected by inhibitors of mPT. We also compared the effects of Ca2+ and Zn2+ in a calcein-retention assay. Consistent with the well-documented ability of Ca2+ to induce mPT, we found that it caused rapid and substantial loss of matrix calcein. In contrast, calcein remained in Zn2+-treated mitochondria. Considered together, our results suggest that Ca2+ and Zn2+ depolarize mitochondria by considerably different mechanisms, that opening of the mPTP is not a direct consequence of Zn2+-induced depolarization, and that Zn2+ is not a particularly potent mitochondrial inhibitor.
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