Guidarelli Andrea, Cerioni Liana, Fiorani Mara, Cantoni Orazio
Dipartimento di Scienze Biomolecolari Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
Int J Mol Sci. 2017 Aug 2;18(8):1686. doi: 10.3390/ijms18081686.
Exposure of U937 cells to peroxynitrite promotes mitochondrial superoxide formation via a mechanism dependent on both inhibition of complex III and increased mitochondrial Ca accumulation. Otherwise inactive concentrations of the oxidant produced the same maximal effects in the presence of either complex III inhibitors or agents mobilizing Ca from the ryanodine receptor and enforcing its mitochondrial accumulation. l-Ascorbic acid (AA) produced similar enhancing effects in terms of superoxide formation, DNA strand scission and cytotoxicity. However, AA failed to enhance the intra-mitochondrial concentration of Ca and the effects observed in cells supplemented with peroxinitrite, while insensitive to manipulations preventing the mobilization of Ca, or the mitochondrial accumulation of the cation, were also detected in human monocytes and macrophages, which do not express the ryanodine receptor. In all these cell types, mitochondrial permeability transition-dependent toxicity was detected in cells exposed to AA/peroxynitrite and, based on the above criteria, these responses also appeared Ca-independent. The enhancing effects of AA are therefore similar to those mediated by bona fide complex III inhibitors, although the vitamin failed to directly inhibit complex III, and in fact enhanced its sensitivity to the inhibitory effects of peroxynitrite.
将U937细胞暴露于过氧亚硝酸根会通过一种依赖于复合体III抑制和线粒体钙积累增加的机制促进线粒体超氧化物的形成。否则，在存在复合体III抑制剂或从兰尼碱受体动员钙并增强其线粒体积累的试剂的情况下，无活性浓度的氧化剂会产生相同的最大效应。L-抗坏血酸（AA）在超氧化物形成、DNA链断裂和细胞毒性方面产生了类似的增强作用。然而，AA未能提高线粒体钙的浓度，并且在补充过氧亚硝酸根的细胞中观察到的效应，在对阻止钙动员或阳离子线粒体积累的操作不敏感的情况下，也在不表达兰尼碱受体的人类单核细胞和巨噬细胞中检测到。在所有这些细胞类型中，在暴露于AA/过氧亚硝酸根的细胞中检测到了线粒体通透性转换依赖性毒性，并且基于上述标准，这些反应也似乎与钙无关。因此，AA的增强作用与真正的复合体III抑制剂介导的作用相似，尽管该维生素未能直接抑制复合体III，实际上还增强了其对过氧亚硝酸根抑制作用的敏感性。
