Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts.
Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts.
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DOI：
10.1016/j.cmet.2014.12.011
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发表时间：
2015-02-03
期刊：
影响因子：
29
通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
--
作者：
Song M;Mihara K;Chen Y;Scorrano L;Dorn GW 2nd
线粒体动力学（分裂和融合）如何影响线粒体质量控制尚不清楚。我们发现抑制Drp 1介导的线粒体分裂与抑制线粒体融合对线粒体自噬有不同的影响。条件性心肌细胞特异性Drp 1消融诱发线粒体增大、致死性扩张型心肌病和心肌细胞坏死。连续消融心肌细胞线粒体融合蛋白（Mfn）引起线粒体碎片离心重构，没有心肌细胞脱落。在培养的小鼠胚胎成纤维细胞（MEFs）和在体内小鼠心脏的平行研究表明，Mfn 1/Mfn 2缺失引起的积累缺陷线粒体表现出未折叠的蛋白质反应，没有适当增加线粒体自噬。相反，中断线粒体分裂的Drp 1消融增加线粒体自噬，并导致线粒体的普遍损失。线粒体通透性转换孔（MPTP）开放在Drp 1空线粒体与线粒体自噬在MEFs和心肌细胞坏死和扩张型心肌病小鼠的贡献。Drp 1、MPTP和心肌细胞线粒体自噬在功能上是整合的。线粒体分裂和融合在体内心脏线粒体质量控制中具有相反的作用。
How mitochondrial dynamism (fission and fusion) affects mitochondrial quality control is unclear. We uncovered distinct effects on mitophagy of inhibiting Drp1-mediated mitochondrial fission versus mitofusin-mediated mitochondrial fusion. Conditional cardiomyocyte-specific Drp1 ablation evoked mitochondrial enlargement, lethal dilated cardiomyopathy, and cardiomyocyte necrosis. Conditionally ablating cardiomyocyte mitofusins (Mfn) caused mitochondrial fragmentation with eccentric remodeling and no cardiomyocyte dropout. Parallel studies in cultured murine embryonic fibroblasts (MEFs) and in vivo mouse hearts revealed that Mfn1/Mfn2 deletion provoked accumulation of defective mitochondria exhibiting an unfolded protein response, without appropriately increasing mitophagy. Conversely, interrupting mitochondrial fission by Drp1 ablation increased mitophagy and caused a generalized loss of mitochondria. Mitochondrial permeability transition pore (MPTP) opening in Drp1 null mitochondria was associated with mitophagy in MEFs and contributed to cardiomyocyte necrosis and dilated cardiomyopathy in mice. Drp1, MPTP, and cardiomyocyte mitophagy are functionally integrated. Mitochondrial fission and fusion have opposing roles during in vivo cardiac mitochondrial quality control.
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影响因子：
20.1
作者：
Chen Y;Csordás G;Jowdy C;Schneider TG;Csordás N;Wang W;Liu Y;Kohlhaas M;Meiser M;Bergem S;Nerbonne JM;Dorn GW 2nd;Maack C
通讯作者：
Maack C
DOI：
10.1073/pnas.0914013107
发表时间：
2010-05-18
影响因子：
11.1
作者：
Chen, Yun;Lewis, William;Dorn, Gerald W., II
通讯作者：
Dorn, Gerald W., II
影响因子：
20.1
作者：
Bhandari P;Song M;Chen Y;Burelle Y;Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
13.3
作者：
Narendra, Derek P.;Kane, Lesley A.;Youle, Richard J.
通讯作者：
Youle, Richard J.
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca