Role of mitofusin 2 in the renal stress response.
Role of mitofusin 2 in the renal stress response.
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DOI：
10.1371/journal.pone.0031074
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bonegio RG
中科院分区：
文献类型：
--
作者：
Gall JM;Wang Z;Liesa M;Molina A;Havasi A;Schwartz JH;Shirihai O;Borkan SC;Bonegio RG
线粒体融合蛋白2（MFN 2）是肾脏应激反应中线粒体形态和功能的关键调节因子，其作用尚不清楚。为了评估其作用，通过Pax2启动子驱动的Cre表达（Pax2Cre）在小鼠肾脏中有条件地缺失MFN2 floxed基因（MFN2 cKO）。MFN2 cKO在肾上皮细胞中引起严重的线粒体断裂，这对正常肾小管功能至关重要。然而，尽管肾单位数量略有减少（20%），但新生cKO幼仔的器官或肾小管功能与同窝Cre阴性幼仔无差异。原代培养的近端小管上皮细胞中MFN2缺乏诱导线粒体碎片化，但未显著改变ATP周转率、最大线粒体氧化储备能力或氰化物暴露期间的低水平耗氧量。MFN2缺陷也没有增加非应激条件下肾小管上皮细胞的凋亡。相比之下，ATP耗竭引起的代谢应激加剧了线粒体外膜损伤，并使MFN2缺陷细胞的凋亡增加了80%。尽管在MFN2缺陷和对照细胞中类似的应激诱导的Bax 6A7表位暴露，但MFN2缺陷显著增加线粒体Bax积累，并且与凋亡诱导因子和细胞色素c的更大释放相关。总之，肾脏MFN 2缺乏导致线粒体片段化，但在发育过程中或非应激条件下不影响肾脏或肾小管功能。然而，MFN2缺陷通过促进线粒体外膜损伤和细胞凋亡而加重肾上皮细胞损伤。
The role of mitofusin 2 (MFN2), a key regulator of mitochondrial morphology and function in the renal stress response is unknown. To assess its role, the MFN2 floxed gene was conditionally deleted in the kidney of mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). MFN2 cKO caused severe mitochondrial fragmentation in renal epithelial cells that are critical for normal kidney tubular function. However, despite a small (20%) decrease in nephron number, newborn cKO pups had organ or tubular function that did not differ from littermate Cre-negative pups. MFN2 deficiency in proximal tubule epithelial cells in primary culture induced mitochondrial fragmentation but did not significantly alter ATP turnover, maximal mitochondrial oxidative reserve capacity, or the low level of oxygen consumption during cyanide exposure. MFN2 deficiency also did not increase apoptosis of tubule epithelial cells under non-stress conditions. In contrast, metabolic stress caused by ATP depletion exacerbated mitochondrial outer membrane injury and increased apoptosis by 80% in MFN2 deficient vs. control cells. Despite similar stress-induced Bax 6A7 epitope exposure in MFN2 deficient and control cells, MFN2 deficiency significantly increased mitochondrial Bax accumulation and was associated with greater release of both apoptosis inducing factor and cytochrome c. In conclusion, MFN2 deficiency in the kidney causes mitochondrial fragmentation but does not affect kidney or tubular function during development or under non-stress conditions. However, MFN2 deficiency exacerbates renal epithelial cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis.
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影响因子：
11.8
作者：
Goyal, Gaurav;Fell, Brennan;Sarin, Apurva;Youle, Richard J.;Sriram, V.
通讯作者：
Sriram, V.
影响因子：
4.5
作者：
Ashrafian H;Docherty L;Leo V;Towlson C;Neilan M;Steeples V;Lygate CA;Hough T;Townsend S;Williams D;Wells S;Norris D;Glyn-Jones S;Land J;Barbaric I;Lalanne Z;Denny P;Szumska D;Bhattacharya S;Griffin JL;Hargreaves I;Fernandez-Fuentes N;Cheeseman M;Watkins H;Dear TN
通讯作者：
Dear TN
影响因子：
7.8
作者：
Goping, I S;Gross, A;Lavoie, J N;Nguyen, M;Jemmerson, R;Roth, K;Korsmeyer, S J;Shore, G C
通讯作者：
Shore, G C
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1073/pnas.0703976104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Brooks, Craig;Wei, Qingqing;Dong, Zheng
通讯作者：
Dong, Zheng