Is complex II involved in the inhibition of mitochondrial respiration by N-methyl-4-phenylpyridinium cation (MMP+) and N-methyl-beta-carbolines?
Is complex II involved in the inhibition of mitochondrial respiration by N-methyl-4-phenylpyridinium cation (MMP+) and N-methyl-beta-carbolines?
复制标题
复合物 II 是否参与 N-甲基-4-苯基吡啶鎓阳离子 (MMP) 和 N-甲基-β-咔啉对线粒体呼吸的抑制？
DOI：
10.1042/bj2910673
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Singer,TP
中科院分区：
文献类型：
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作者：
Krueger,MJ;Tan,AK;Ackrell,BA;Singer,TP
据报道，神经毒性n -甲基-4-苯基吡啶离子（MPP+）的n -甲基- β -碳鎓类似物对nadh相关的线粒体氧化以及琥珀酸盐对线粒体呼吸的抑制程度几乎相同[Fields， Albores， Neafsey和Collins (1992) Arch。物化学。生物工程学报，2004,23(2):444 - 444。这些作者进一步声称，MPP+本身除了对NADH脱氢酶（复合体I）的众所周知的作用外，还通过琥珀酸脱氢酶阻断呼吸，并得出结论，这两种作用可能有助于帕金森症状的发展。由于n -甲基- β -碳元素被认为是内源性代谢物，如果这些发现得到证实，将对特发性帕金森病的病因学产生重要影响。我们使用琥珀酸脱氢酶完全激活后的线粒体以及不存在膜运输复杂性的亚线粒体颗粒重新检查了这些观察结果。我们报告以下观察结果。(1) n -甲基- β -碳碱以时间依赖性的方式抑制NAD（+）连接底物上的线粒体呼吸，并且与预期的正电荷化合物一样，四苯基硼阴离子（TPB-）的存在增强了这种抑制作用。(2)然而，与MPP+本身不同的是，这些化合物在较高浓度下是解偶联剂，因此在状态3中看到的效果不能完全归因于抑制NADH氧化。(3)对线粒体琥珀酸氧化的影响比通过复合体I对呼吸的影响低1-1.5个数量级，因此不太可能对神经毒性有显著贡献。(4) MPP+通过琥珀酸脱氢酶对线粒体呼吸的影响微不足道，与之前几个实验室的报告一致，但与Fields等人的发现相矛盾（上文引用）。(5)在亚线粒体颗粒中，NADH氧化的抑制（通过全呼吸链）已被证实，但它与MPP+的作用在两个方面有明显不同。首先，城规会-的改善作用非常小；其次，使用泛醌(Q)类似物测量对NADH氧化的抑制作用要低得多，这表明复合物I不是唯一的目标。(6)在亚线粒体颗粒中，O2或Q类似物对琥珀酸盐氧化的抑制是不完全的、微不足道的或不存在的。(7)因此，我们得出的结论是，我们没有发现将n -甲基- β -碳鎓化合物的任何潜在生物学效应归因于琥珀酸盐氧化的阻断的依据。
It has been reported that N-methyl-beta-carbolinium analogues of the neurotoxic N-methyl-4-phenylpyridinium cation (MPP+) inhibit NADH-linked mitochondrial oxidations, as well as mitochondrial respiration on succinate nearly to the same extent [Fields, Albores, Neafsey and Collins (1992) Arch. Biochem. Biophys. 294, 539-544]. Those authors further claimed that MPP+ itself also blocks respiration through succinate dehydrogenase, in addition to its well-known effect on NADH dehydrogenase (Complex I), and concluded that both effects may contribute to the development of Parkinsonian symptoms. Since N-methyl-beta-carboliniums are thought to be endogenous metabolites, these findings, if verified, would have important implications on the etiology of idiopathic Parkinsonism. We have re-examined these observations, using mitochondria after full activation of succinate dehydrogenase, as well as submitochondrial particles, in which complexities due to membrane transport are not present. We report the following observations. (1) N-Methyl-beta-carboliniums inhibit mitochondrial respiration on NAD(+)-linked substrates in a time-dependent manner, and the inhibition is potentiated by the presence of tetraphenylboron anion (TPB-), as expected for positively charged compounds. (2) Unlike MPP+ itself, however, these compounds are uncouplers at higher concentrations, so that the effects seen in State 3 cannot be assigned exclusively to inhibition of NADH oxidation. (3) The effects on succinate oxidation in mitochondria, in which the full activity of the enzyme is expressed, are 1-1.5 orders of magnitude lower than on respiration via Complex I and are thus unlikely to contribute significantly to the neurotoxicity. (4) The effect of MPP+ on mitochondrial respiration via succinate dehydrogenase is trivial, in accord with previous reports from several laboratories, but contradicting the findings of Fields et al. (cited above). (5) In submitochondrial particles the inhibition of NADH oxidation (via the complete respiratory chain) has been confirmed, but it differs markedly from the action of MPP+ in two respects. First, the enhancement by TPB- is very small; secondly, the inhibition of NADH oxidation measured using ubiquinone (Q) analogues is far lower, suggesting that Complex I is not the only target. (6) In submitochondrial particles the inhibition of succinate oxidation by either O2 or Q analogues is incomplete, trivial or absent. (7) We thus conclude that we find no basis for assigning any potential biological effect of N-methyl-beta-carboliniums to the blockade of succinate oxidation.