Porphyrin accumulation in mitochondria is mediated by 2-oxoglutarate carrier
Porphyrin accumulation in mitochondria is mediated by 2-oxoglutarate carrier
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DOI：
10.1074/jbc.m604729200
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发表时间：
2006-10-20
影响因子：
4.8
通讯作者：
Handa, Hiroshi
中科院分区：
文献类型：
--
作者：
Kabe, Yasuaki;Ohmori, Masashi;Handa, Hiroshi
血红素（Fe-protoporphyrin IX）是一种内源性卟啉衍生物，是有氧生物必需的分子，在氧气运输、呼吸和信号转导等多种生理过程中发挥作用。对于血红素或线粒体血红素蛋白的生物合成，血红素或其生物合成前体卟啉必须从细胞质转运到线粒体。卟啉在线粒体内膜积聚的机制尚不清楚。在本研究中，我们分析了卟啉衍生物线粒体易位的机制。我们发现钯中四（4-羧基苯基）卟啉（PdTCPP）是一种磷光卟啉衍生物，在几种细胞系的线粒体中积累。使用亲和乳胶珠，我们发现2-氧戊二酸载体（OGC），即2-氧戊二酸的线粒体转运体，与PdTCPP结合，并且在体外PdTCPP以竞争方式抑制2-氧戊二酸进入线粒体（K-i = 15 μ M）。有趣的是，本研究中检测的所有类型的卟啉衍生物竞争性地抑制线粒体对2-氧葡萄糖酸盐的摄取，包括原卟啉IX、共比例卟啉III和血红蛋白。此外，2-氧葡萄糖酸酯或OGC抑制剂可抑制线粒体卟啉的积累。这些结果表明，卟啉在线粒体中的积累是由OGC介导的，卟啉能够竞争性地抑制2-氧葡萄糖酸盐摄取到线粒体。这是第一个关于卟啉在线粒体内膜积累的推测机制的报道。
Heme (Fe-protoporphyrin IX), an endogenous porphyrin derivative, is an essential molecule in living aerobic organisms and plays a role in a variety of physiological processes such as oxygen transport, respiration, and signal transduction. For the biosynthesis of heme or the mitochondrial heme proteins, heme or its biosynthetic precursor porphyrin must be transported into mitochondria from cytosol. The mechanism of porphyrin accumulation in the mitochondrial inner membrane is unclear. In the present study, we analyzed the mechanism of mitochondrial translocation of porphyrin derivatives. We showed that palladium meso-tetra(4-carboxyphenyl) porphyrin (PdTCPP), a phosphorescent porphyrin derivative, accumulated in the mitochondria of several cell lines. Using affinity latex beads, we showed that 2-oxoglutarate carrier (OGC), the mitochondrial transporter of 2-oxoglutarate, bound to PdTCPP, and in vitro PdTCPP-inhibited 2-oxoglutarate uptake into mitochondria in a competitive manner (K-i = 15 mu M). Interestingly, all types of porphyrin derivatives examined in this study competitively inhibited 2-oxoglutarate uptake into mitochondria, including protoporphyrin IX, coproporphyrin III, and hemin. Furthermore, mitochondrial accumulation of porphyrins was inhibited by 2-oxoglutarate or OGC inhibitor. These results suggested that porphyrin accumulation in mitochondria is mediated by OGC and that porphyrins are able to competitively inhibit 2-oxoglutarate uptake into mitochondria. This is the first report of a putative mechanism for accumulation of porphyrins in the mitochondrial inner membrane.