Differential cytotoxicity of Mn(II) and Mn(III): Special reference mitochondrial [Fe-S] containing enzymes
Differential cytotoxicity of Mn(II) and Mn(III): Special reference mitochondrial [Fe-S] containing enzymes
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DOI：
10.1006/taap.2001.9245
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发表时间：
2001-09-01
影响因子：
3.8
通讯作者：
Zheng, W
中科院分区：
文献类型：
--
作者：
Chen, JY;Tsao, GC;Zheng, W
锰 (Mn) 诱导的神经退行性毒性与全身和细胞水平上的铁 (Fe) 代谢紊乱有关。在当前的研究中，我们在体外检查了 Mn 的氧化态是否对某些含有 [Fe-S] 的线粒体酶产生不同的影响。当具有 [4Fe-4S] 簇的线粒体乌头酸酶与 Mn(II) 或 Mn(III) 一起孵育时，两种 Mn 都会抑制乌头酸酶的活性。然而，Mn(HI) 的 IC10（引起 10% 酶抑制的浓度）比 Mn(II) 低九倍。将线粒体部分暴露于 Mn(II) 或 Mn(III) 后，任一 Mn 物质都会显着抑制复合物 I 的活性，复合物 I 的活性位点包含 5 至 8 个 [Fe-S] 簇。剂量-时间响应曲线表明，Mn(III) 在阻断复合物 I 活性方面比 Mn(II) 更有效。 Northern blotting 用于检测编码转铁蛋白受体 (TfR) 的 mRNA 表达，该受体受胞质顺乌头酸酶调节。用 100 muM Mn(II) 和 Mn(III) 处理培养的 PC12 细胞 3 天，导致 TfR mRNA 的表达分别增加 21% 和 58%。对暴露于培养基中的 25-50 muM Mn 后的细胞生长动力学的进一步研究表明，与 Mn(II) 处理组相比，Mn(III) 处理组的细胞数量大大减少，表明 Mn(III) 比 Mn(II) 杀伤细胞更有效。在暴露于 Mn(II) 和 Mn(IH) 的细胞中，线粒体 DNA (mtDNA) 分别显着减少 24% 和 16%。相比之下，鱼藤酮和 MPP+ 似乎没有改变 mtDNA 水平。这些体外结果表明，Mn(IH) 物质似乎比 Mn(II) 物质更具细胞毒性，可能是由于更高的氧化反应性和与 Fe 更接近的半径。 (C) 2001 年学术出版社。
Manganese (Mn)-induced neurodegenerative toxicity has been associated with a distorted iron (Fe) metabolism at both systemic and cellular levels. In the current study, we examined whether the oxidation states of Mn produced differential effects on certain mitochondrial [Fe-S] containing enzymes in vitro. When mitochondrial aconitase, which possesses a [4Fe-4S] cluster, was incubated with either Mn(II) or Mn(III), both Mn species inhibited the activities of aconitase. However, the IC10 (concentration to cause a 10% enzyme inhibition) for Mn(HI) was ninefold lower than that for Mn(II). Following exposure of mitochondrial fractions with Mn(II) or Mn(III), there was a significant inhibition by either Mn species in activities of Complex I whose active site contains five to eight [Fe-S] clusters. The dose-time response curves reveal that Mn(III) was more effective in blocking Complex I activity than Mn(II). Northern blotting was used to examine the expression of mRNAs encoding transferrin receptor (TfR), which is regulated by cytosolic aconitase. Treatment of cultured PC12 cells with Mn(II) and Mn(III) at 100 muM for 3 days resulted in 21 and 58% increases, respectively, in the expression of TfR mRNA. Further studies on cell growth dynamics after exposure to 25-50 muM Mn in culture media demonstrated that the cell numbers were much reduced in Mn(III)- treated groups compared to Mn(II)-treated groups, suggesting that Mn(III) is more effective than Mn(II) in cell killing. In cells exposed to Mn(II) and Mn(IH), mitochondrial DNA (mtDNA) was significantly decreased by 24 and 16%, respectively. In contrast, rotenone and MPP+ did not seem to alter mtDNA levels. These in vitro results suggest that Mn(IH) species appears to be more cytotoxic than Mn(II) species, possibly due to higher oxidative reactivity and closer radius resemblance to Fe. (C) 2001 Academic Press.