Mechanisms of berberine (Natural Yellow 18)-induced mitochondrial dysfunction: Interaction with the adenine nucleotide translocator
Mechanisms of berberine (Natural Yellow 18)-induced mitochondrial dysfunction: Interaction with the adenine nucleotide translocator
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DOI：
10.1093/toxsci/kfn131
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发表时间：
2008-10-01
影响因子：
3.8
通讯作者：
Oliveira, Paulo J.
中科院分区：
文献类型：
--
作者：
Pereira, Claudia V.;Machado, Nuno G.;Oliveira, Paulo J.
小檗碱[天然黄色18,5,6 -二氢-9,10-二甲氧基苯并(g)-1,3-苯二氮唑（5,6-a）喹啉]是一种存在于小檗科植物中的生物碱，在中国和北美的传统药物中使用。我们之前已经证明，小檗碱导致线粒体去极化和分裂，同时增加氧化应激。我们还证明了小檗碱通过诱导线粒体通透性转变（MPT）导致线粒体呼吸抑制和钙负荷能力降低。本研究的目的是研究MPT诱导和呼吸抑制的共同靶点。假设是小檗碱通过与腺嘌呤核苷酸转运子（ANT）相互作用诱导MPT。通过测量线粒体肿胀增加、膜去极化和钙潴留丧失对MPT的诱导作用，我们观察到小檗碱的作用不受bongkrekic酸的抑制，尽管二磷酸腺苷(ADP)/寡霉素完全阻止了MPT。此外，我们还观察到小檗碱增加了油酸对肝脏线粒体的去极化作用。当小檗碱加入线粒体时，观察到的初始去极化不受ANT抑制剂的影响。综上所述，我们认为小檗碱作用于蚂蚁，改变了蛋白质与bongkrekic酸的结合，而不是与环孢素A或ADP的结合。同样清楚的是，膜电位是小檗碱作用所必需的，很可能是为了允许其线粒体积累。小檗碱的线粒体效应不仅与其提出的抗肿瘤活性有关，而且与评估其器官毒性有关，这取决于组织积累或输送等因素。
Berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo (5,6-a) quinolizinium] is an alkaloid present in plants of the Berberidaceae family and used in traditional Chinese and North American medicine. We have previously demonstrated that berberine causes mitochondrial depolarization and fragmentation, with simultaneous increase in oxidative stress. We also demonstrated that berberine causes an inhibition of mitochondrial respiration and a decrease on calcium loading capacity through induction of the mitochondrial permeability transition (MPT). The objective of the present work is to investigate a common target for both induction of the MPT and inhibition of respiration. The hypothesis is that berberine induces the MPT through interacting with the adenine nucleotide translocator (ANT). By measuring induction of the MPT through increased mitochondrial swelling, membrane depolarization and loss of calcium retention, we observed that the effects of berberine were not inhibited by bongkrekic acid although adenosine diphosphate (ADP)/oligomycin completely prevented the MPT. Also, we observed that berberine increased the depolarization effect of oleic acid on liver mitochondria. The initial depolarization observed when berberine is added to mitochondria was not affected by ANT inhibitors. Taken together, we propose that berberine acts on the ANT, altering the binding of the protein to bongkrekic acid but not to cyclosporin A or ADP. It is also clear that the membrane potential is required for berberine effects, most likely for allowing for its mitochondrial accumulation. Mitochondrial effects of berberine can be relevant not only for its proposed antitumor activity but also for the assessment of its organ toxicity, depending on factors such as tissue accumulation or delivery.