ATP-dependent Mitochondrial Porphyrin Importer ABCB6 Protects against Phenylhydrazine Toxicity
ATP-dependent Mitochondrial Porphyrin Importer ABCB6 Protects against Phenylhydrazine Toxicity
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DOI：
10.1074/jbc.m111.336180
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发表时间：
2012-04-13
影响因子：
4.8
通讯作者：
Schuetz, John D.
中科院分区：
文献类型：
--
作者：
Ulrich, Dagny L.;Lynch, John;Schuetz, John D.
Abcb 6是哺乳动物线粒体ATP结合盒（ABC）转运蛋白，调节从头卟啉合成。在以前的研究中，单倍不足（Abcb 6（+/-））胚胎干细胞显示受损的卟啉合成。出乎意料的是，从这些干细胞衍生的Abcb 6（-/-）小鼠表现出表型正常。我们假设，其他ATP依赖性和/或非依赖性机制保存卟啉。在这里，我们证明了Abcb 6（-/-）小鼠缺乏线粒体ATP驱动的粪卟啉III的进口。基因表达分析表明，Abcb 6的损失导致补偿性卟啉和铁途径的上调，与升高的原卟啉IX（PPIX）相关。苯肼诱导的应激导致Abcb 6（-/-）小鼠的死亡率较高，可能是因为PPIX持续升高，尽管亚铁螯合酶水平升高，但PPIX无法转化为血红素。因此，Abcb 6是唯一的ATP依赖性卟啉进口商，和Abcb 6的损失产生正常发育所需的血红素和铁途径的上调。然而，在对卟啉的极端需求（例如苯肼应激）下，这些适应似乎不足，这表明在这些条件下Abcb 6对于最佳存活是重要的。
Abcb6 is a mammalian mitochondrial ATP-binding cassette (ABC) transporter that regulates de novo porphyrin synthesis. In previous studies, haploinsufficient (Abcb6(+/-)) embryonic stem cells showed impaired porphyrin synthesis. Unexpectedly, Abcb6(-/-) mice derived from these stem cells appeared phenotypically normal. We hypothesized that other ATP-dependent and/or -independent mechanisms conserve porphyrins. Here, we demonstrate that Abcb6(-/-) mice lack mitochondrial ATP-driven import of coproporphyrin III. Gene expression analysis revealed that loss of Abcb6 results in up-regulation of compensatory porphyrin and iron pathways, associated with elevated protoporphyrin IX (PPIX). Phenylhydrazine-induced stress caused higher mortality in Abcb6(-/-) mice, possibly because of sustained elevation of PPIX and an inability to convert PPIX to heme despite elevated ferrochelatase levels. Therefore, Abcb6 is the sole ATP-dependent porphyrin importer, and loss of Abcb6 produces up-regulation of heme and iron pathways necessary for normal development. However, under extreme demand for porphyrins (e.g. phenylhydrazine stress), these adaptations appear inadequate, which suggests that under these conditions Abcb6 is important for optimal survival.