Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Int J Mol Sci. 2021 Apr 17;22(8):4172. doi: 10.3390/ijms22084172.
Mitochondria are well-known to function as the primary sites of ATP synthesis in most mammalian cells, including the renal proximal tubule. Other functions have also been associated with different mitochondrial activities, including the regulation of redox status and the initiation of mitophagy and apoptosis. Mechanisms for the membrane transport of glutathione (GSH) and various GSH-derived metabolites across the mitochondrial inner membrane of renal proximal tubular cells are critical determinants of these functions and may serve as pharmacological targets for potential therapeutic approaches. Specific interactions of reactive intermediates, derived from drug metabolism, with molecular components in mitochondria have been identified as early steps in diverse forms of chemically-induced nephrotoxicity. Applying this key observation, we developed a novel hypothesis regarding the identification of early, sensitive, and specific biomarkers of exposure to nephrotoxicants. The underlying concept is that upon exposure to a diverse array of environmental contaminants, as well as therapeutic drugs whose efficacy is limited by nephrotoxicity, renal mitochondria will release both high- and low-molecular-weight components into the urine or the extracellular medium in an in vitro model. The detection of these components may then serve as indicators of exposure before irreversible renal injury has occurred.
线粒体是大多数哺乳动物细胞中 ATP 合成的主要场所，包括肾近端小管。其他功能也与不同的线粒体活动有关，包括氧化还原状态的调节以及自噬和细胞凋亡的启动。谷胱甘肽 (GSH) 和各种 GSH 衍生代谢物穿过肾近端小管细胞线粒体内膜的膜转运机制是这些功能的关键决定因素，并且可能成为潜在治疗方法的药理学靶点。来自药物代谢的反应性中间体与线粒体中分子成分的特定相互作用已被确定为多种化学诱导性肾毒性的早期步骤。应用这一关键观察结果，我们提出了一个关于鉴定接触肾毒性物质的早期、敏感和特异性生物标志物的新假设。其基本概念是，在接触各种环境污染物以及因肾毒性而疗效受限的治疗性药物时，肾线粒体将在体外模型中将高分子和低分子质量成分同时释放到尿液或细胞外介质中。然后，这些成分的检测可以作为暴露的指标，而在不可逆的肾损伤发生之前。
