Mitochondrial glutathione transport: Physiological, pathological and toxicological implications
Mitochondrial glutathione transport: Physiological, pathological and toxicological implications
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DOI：
10.1016/j.cbi.2006.03.001
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发表时间：
2006-10-27
影响因子：
5.1
通讯作者：
Lash, Lawrence H.
中科院分区：
文献类型：
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作者：
Lash, Lawrence H.
虽然大多数细胞谷胱甘肽(GSH)存在于细胞质中，但线粒体中存在一个明显受调控的池。由于谷胱甘肽的合成主要局限于细胞质，线粒体池必须来自细胞质-谷胱甘肽跨线粒体内膜的运输。早期对肝脏线粒体的研究主要集中在GSH状态与膜通透性和能量学之间的关系。由于GSH在生理pH下是一个阴离子，这表明存在于内膜上的一些有机阴离子载体可能在GSH转运中起作用。事实上，Lash和他的同事在分离的大鼠肾脏线粒体中的研究表明，该组织中的大部分转运(>；80%)可以由二羧酸盐载体(DIC，Slc25a10)和草戊二酸载体(OGC，Slc25a11)的功能所解释，这两种载体分别介导二羧酸盐与无机磷的电子中和交换，以及2-氧戊二酸与其他二羧酸盐的电子中和交换。尽管OGC在心脏、肝脏和脑中表达，DIC在肝脏和肾脏中表达，但特定载体蛋白在其他组织中的特性和功能尚不确定。另一种运输2-氧戊二酸的载体，即氧二羧酸或氧己二酸载体(ODC；Slc25a21)，已经在大鼠和人的肝脏中被描述，它的表达具有广泛的组织分布，尽管它在GSH运输中的潜在功能还没有被研究。DIC和OGC在肾近端小管源性细胞系NRK-52E细胞中的过表达表明，载体表达和活性的增强对氧化应激和化学诱导的细胞凋亡具有保护作用。这对于开发治疗人类疾病和病理状态的新的治疗方法具有重要意义。几种情况，如酒精性肝病、肝硬变或其他慢性胆道梗阻性疾病，以及糖尿病肾病，都与肝或肾中线粒体GSH池的耗尽或氧化有关。(C)2006爱思唯尔爱尔兰有限公司。保留所有权利。
Although most cellular glutathione (GSH) is in the cytoplasm, a distinctly regulated pool is present in mitochondria. Inasmuch as GSH synthesis is primarily restricted to the cytoplasm, the mitochondrial pool must derive from transport of cytoplasmic-GSH across the mitochondrial inner membrane. Early studies in liver mitochondria primarily focused on the relationship between GSH status and membrane permeability and energetics. Because GSH is an anion at physiological pH, this suggested that some of the organic anion carriers present in the inner membrane could function in GSH transport. Indeed, studies by Lash and colleagues in isolated mitochondria from rat kidney showed that most of the transport (> 80%) in that tissue could be accounted for by function of the dicarboxylate carrier (DIC, Slc25a10) and the oxoglutarate carrier (OGC, Slc25a11), which mediate electroneutral exchange of dicarboxylates for inorganic phosphate and 2-oxoglutarate for other dicarboxylates, respectively. The identity and function of specific carrier proteins in other tissues is less certain, although the OGC is expressed in heart, liver, and brain and the DIC is expressed in liver and kidney. An additional carrier that transports 2-oxoglutarate, the oxodicarboxylate or oxoadipate carrier (ODC; Slc25a21), has been described in rat and human liver and its expression has a wide tissue distribution, although its potential function in GSH transport has not been investigated. Overexpression of the cDNA for the DIC and OGC in a renal proximal tubule-derived cell line, NRK-52E cells, showed that enhanced carrier expression and activity protects against oxidative stress and chemically induced apoptosis. This has implications for development of novel therapeutic approaches for treatment of human diseases and pathological states. Several conditions, such as alcoholic liver disease, cirrhosis or other chronic biliary obstructive diseases, and diabetic nephropathy, are associated with depletion or oxidation of the mitochondrial GSH pool in liver or kidney. (c) 2006 Elsevier Ireland Ltd. All rights reserved.