Renal cold storage followed by transplantation impairs expression of key mitochondrial fission and fusion proteins.
Renal cold storage followed by transplantation impairs expression of key mitochondrial fission and fusion proteins.
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DOI：
10.1371/journal.pone.0185542
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
MacMillan-Crow LA
中科院分区：
文献类型：
--
作者：
Parajuli N;Shrum S;Tobacyk J;Harb A;Arthur JM;MacMillan-Crow LA
大多数移植肾是从死亡的供体获得的，这些供体都需要暴露于冷藏（CS）以成功移植。不幸的是，这种CS导致肾脏和线粒体损伤，但受CS影响的特定线粒体靶点在很大程度上仍然未知。本研究的目的是确定是否涉及线粒体融合或分裂的途径，在肾CS中断。将雄性刘易斯大鼠肾脏暴露于单独冷藏（CS）或冷藏与移植联合（CS/Tx）。为了比较CS诱导的效应，还使用了无CS暴露的肾移植（自体移植; ATx）。使用高分辨率呼吸测定法评估线粒体功能。使用Western印迹分析监测线粒体融合和分裂蛋白的表达。CS单独（无Tx）降低呼吸复合物I和II活性，沿着初级线粒体分裂蛋白、发动蛋白相关蛋白（DRP 1）的表达降低，诱导长型视神经萎缩蛋白（OPA 1）的丢失，并改变调节OPA 1加工的线粒体蛋白酶OMA 1。CS随后Tx（CS/Tx）降低复合物I、II和III的活性，并诱导长和短形式的OPA 1、线粒体融合蛋白1（MFN 1）和线粒体融合蛋白2（MFN 2）的严重损失，所述OPA 1、线粒体融合蛋白1和线粒体融合蛋白2都控制线粒体融合。此外，DRP 1的表达，沿着其主要受体蛋白，线粒体分裂因子（MFF），也减少后CS/Tx。有趣的是，CS/Tx导致异常的较高分子量的OMA 1聚集体表达。我们的研究结果表明，CS似乎涉及激活OMA 1，这可能是一个关键的球员在蛋白质水解的融合和分裂蛋白机器移植后。这些发现提出了这样的可能性，即受损的线粒体分裂和融合可能是CS诱导的线粒体损伤和移植后移植肾功能受损的未被识别的贡献者。
The majority of transplanted kidneys are procured from deceased donors which all require exposure to cold storage (CS) for successful transplantation. Unfortunately, this CS leads to renal and mitochondrial damage but, specific mitochondrial targets affected by CS remain largely unknown. The goal of this study is to determine whether pathways involved with mitochondrial fusion or fission, are disrupted during renal CS. Male Lewis rat kidneys were exposed to cold storage (CS) alone or cold storage combined with transplantation (CS/Tx). To compare effects induced by CS, kidney transplantation without CS exposure (autotransplantation; ATx) was also used. Mitochondrial function was assessed using high resolution respirometry. Expression of mitochondrial fusion and fission proteins were monitored using Western blot analysis. CS alone (no Tx) reduced respiratory complex I and II activities along with reduced expression of the primary mitochondrial fission protein, dynamin related protein (DRP1), induced loss of the long form of Optic Atrophy Protein (OPA1), and altered the mitochondrial protease, OMA1, which regulates OPA1 processing. CS followed by Tx (CS/Tx) reduced complex I, II, and III activities, and induced a profound loss of the long and short forms of OPA1, mitofusin 1 (MFN1), and mitofusin 2 (MFN2) which all control mitochondrial fusion. In addition, expression of DRP1, along with its primary receptor protein, mitochondrial fission factor (MFF), were also reduced after CS/Tx. Interestingly, CS/Tx lead to aberrant higher molecular weight OMA1 aggregate expression. Our results suggest that CS appears to involve activation of the OMA1, which could be a key player in proteolysis of the fusion and fission protein machinery following transplantation. These findings raise the possibility that impaired mitochondrial fission and fusion may be unrecognized contributors to CS induced mitochondrial injury and compromised renal graft function after transplantation.
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作者：
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DOI：
10.1124/jpet.110.176743
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