Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow
Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow
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DOI：
10.1073/pnas.94.10.4890
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Kesler, N
中科院分区：
文献类型：
--
作者：
Cohen, G;Farooqui, R;Kesler, N
导致帕金森病进展的两个因素是大脑线粒体呼吸缺陷和单胺氧化酶 (MAO) 产生过氧化氢 (H2O2)，在这里我们表明两者是相关的，完整的大鼠脑线粒体抑制神经递质多巴胺或其他单胺（苯甲胺、酪胺）的代谢 丙酮酸和琥珀酸依赖性电子传递，MAO抑制剂可阻止这种作用，线粒体损伤在电子流动过程中也会逆转，一个可能的解释是MAO产生的H2O2将谷胱甘肽氧化为谷胱甘肽二硫化物（GSSG），后者经历硫醇-二硫化物交换形成蛋白质混合二硫化物，从而可逆地干扰 硫醇依赖性酶功能，与此前提一致，将 GSSG 直接添加到线粒体会导致类似的电子传递可逆抑制，此外，单胺诱导线粒体内蛋白质混合二硫化物的升高，这些观察结果表明（i）单胺神经元神经递质的活性和代谢增强可能会影响神经元功能，并且 （ii）与帕金森病相关的线粒体呼吸的明显缺陷可能部分反映了多巴胺周转率的增加。实验结果还针对线粒体修复机制进行进一步研究，并可能最终导致更新形式的治疗。
Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO), Here we show that the two are linked, Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport, MAO inhibitors prevent this action, Mitochondrial damage is also reversed during electron flow, A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function, In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport, In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria, These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover, The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.