Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead
Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead
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线粒体通透性转变及其调节成分与暴露于铅的大鼠近端肾小管细胞原代培养物的凋亡有关
DOI：
10.1007/s00204-015-1547-0
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发表时间：
2016-05-01
影响因子：
6.1
通讯作者：
Wang, Lin
中科院分区：
文献类型：
--
作者：
Liu, Gang;Wang, Zhong-Kun;Wang, Lin
先前的研究已经表明，线粒体在铅诱导的大鼠近端肾小管（rPT）细胞原代培养的凋亡中起着关键作用。为了进一步阐明铅诱导线粒体凋亡的机制，本研究旨在探讨线粒体通透性转换（MPT）及其调控成分在铅诱导rPT细胞凋亡中的作用。本研究观察到线粒体通透性转换孔（MPTP）开放、线粒体超微结构破坏、细胞色素从线粒体移位到胞浆以及随后的caspase-3激活，提示MPT参与了铅诱导的rPT细胞凋亡。3种MPTP抑制剂CsA、DIDS、BA分别作用于MPTP的不同调控组分Cyp-D、VDAC、ANT，均可显著抑制铅诱导的caspase-3活化和细胞凋亡，表明Cyp-D、VDAC和ANT参与了铅暴露对MPTP的调控。此外，铅处理引起的ATP水平降低和ADP/ATP比值升高可被BA显著逆转，表明铅介导的ANT功能障碍导致ATP耗竭。此外，在铅暴露条件下，rPT细胞中VDAC-1、ANT-1的表达上调，Cyp-D、VDAC-2和ANT-2的表达下调。总之，铅介导的线粒体凋亡在rPT细胞是依赖于MPTP开放。不同的表达水平，在每个异构体的三个调节组件有助于改变其功能，这可能会促进MPTP开放。
Previous studies have already demonstrated that mitochondria play a key role in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells. To further clarify the underlying mechanism of Pb-induced mitochondrial apoptosis, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and its regulatory components in Pb-induced apoptosis in rPT cells. Mitochondrial permeability transition pore (MPTP) opening together with disruption of mitochondrial ultrastructure, translocation of cytochromecfrom mitochondria to cytoplasm and subsequent caspase-3 activation were observed in this study, suggesting that MPT is involved in Pb-induced apoptosis in rPT cells. Simultaneously, Pb-induced caspase-3 activation and apoptosis can be significantly inhibited by three MPTP inhibitors (CsA, DIDS, BA), which target different regulatory components of MPTP (Cyp-D, VDAC, ANT), respectively, demonstrating that Cyp-D, VDAC and ANT participate in MPTP regulation during lead exposure. Moreover, decreased ATP levels and increased ADP/ATP ratio induced by lead treatment can be significantly reversed by BA, indicating that Pb-mediated ANT dysfunction resulted in ATP depletion. In addition, up-regulation of VDAC-1, ANT-1 together with down-regulation of Cyp-D, VDAC-2 and ANT-2 at both the levels of transcription and translation were revealed in rPT cells under lead exposure conditions. In conclusion, Pb-mediated mitochondrial apoptosis in rPT cells is dependent on MPTP opening. Different expression levels in each isoform of three regulatory components contribute to alteration in their functions, which may promote the MPTP opening.