Aluminum as an inducer of the mitochondrial permeability transition
Aluminum as an inducer of the mitochondrial permeability transition
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DOI：
10.1007/s007750000144
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发表时间：
2000-10
期刊：
影响因子：
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通讯作者：
A. Toninello;G. Clari;M. Mancon;G. Tognon;P. Zatta
中科院分区：
文献类型：
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作者：
A. Toninello;G. Clari;M. Mancon;G. Tognon;P. Zatta
在Ca 2+存在下用铝处理大鼠肝线粒体导致大幅度肿胀，伴随着内源性Mg 2+和K+的损失和内源性吡啶核苷酸的氧化。环孢菌素A，二磷酸腺苷，bongkrekic酸，N-乙基马来酰亚胺和dithiocyanate的存在下，防止这些影响，表明铝的结合线粒体内膜，最有可能在腺嘌呤核苷酸转位酶的水平，与膜通透性转换（MPT）的诱导。事实上，铝的结合促进了泛喹啉-细胞色素还原酶水平的扰动，这有利于活性氧的产生。这些代谢产物产生氧化应激，涉及与谷胱甘肽和吡啶核苷酸库平衡的两个先前定义的位点，其水平与MPT诱导的增加相关。尽管上述现象是MPT的典型现象，但它们不被通常在响应于用MPT诱导剂治疗时观察到的其他事件（例如，磷酸盐），如电化学梯度的崩溃和积累的Ca 2+和氧化的吡啶核苷酸的释放。生物化学和超微结构的观察表明，铝诱导的孔开放具有完全开放和关闭的线粒体亚群之间的构象中间。虽然无机磷酸盐增强了钌红加去能剂诱导的MPT，但铝反而抑制了这种现象。这一发现表明，存在一个独特的结合位点的铝不同参与MPT诱导。
Treatment of rat liver mitochondria with aluminum in the presence of Ca2+results in large amplitude swelling accompanied by loss of endogenous Mg2+and K+and oxidation of endogenous pyridine nucleotides. The presence of cyclosporin A, ADP, bongkrekic acid,N-ethylmaleimide and dithioerythritol prevent these effects, indicating that binding of aluminum to the inner mitochondrial membrane, most likely at the level of adenine nucleotide translocase, correlates with the induction of the membrane permeability transition (MPT). Indeed, aluminum binding promotes such a perturbation at the level of ubiquinol-cytochromecreductase, which favors the production of reactive oxygen species. These metabolites generate an oxidative stress involving two previously defined sites in equilibrium with the glutathione and pyridine nucleotides pools, the levels of which correlate with the increase in MPT induction. Although the above-described phenomena are typical of MPT, they are not paralleled by other events normally observed in response to treatment with inducers of MPT (e.g., phosphate), such as the collapse of the electrochemical gradient and the release of accumulated Ca2+and oxidized pyridine nucleotides. Biochemical and ultrastructural observations demonstrate that aluminum induces a pore opening having a conformation intermediate between fully open and closed in a subpopulation of mitochondria. While inorganic phosphate enhances the MPT induced by ruthenium red plus a deenergizing agent, aluminum instead inhibits this phenomenon. This finding suggests the presence of a distinct binding site for aluminum differing from that involved in MPT induction.