Regulation of mitochondrial morphogenesis by annexin A6.
Regulation of mitochondrial morphogenesis by annexin A6.
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DOI：
10.1371/journal.pone.0053774
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Moss SE
中科院分区：
文献类型：
--
作者：
Chlystun M;Campanella M;Law AL;Duchen MR;Fatimathas L;Levine TP;Gerke V;Moss SE
线粒体稳态在满足细胞能量需求、形成钙信号和确定对凋亡的易感性方面是至关重要的。在这里，我们报告的作用，在线粒体形态发生的调节anxA 6，并表明，在细胞缺乏anxA 6线粒体片段化，呼吸受损，线粒体膜电位降低。在AnxA 6 −/−小鼠的成纤维细胞中，线粒体Ca 2+摄取减少，胞质Ca 2+瞬变升高。这些观察结果使我们研究了anxA 6和在线粒体融合和裂变中起作用的蛋白质之间可能的相互作用。我们发现anxA 6与Drp 1相关，并且Drp 1抑制剂mdivi-1阻止了AnxA 6 −/−成纤维细胞中的线粒体片段化。在正常细胞中，细胞内Ca 2+的升高破坏了anxA 6和Drp 1之间的相互作用，将anxA 6置换到质膜并促进线粒体分裂。我们的研究结果表明，anxA 6抑制Drp 1活性，钙离子结合anxA 6缓解这种抑制，允许Drp 1介导的线粒体分裂。
Mitochondrial homeostasis is critical in meeting cellular energy demands, shaping calcium signals and determining susceptibility to apoptosis. Here we report a role for anxA6 in the regulation of mitochondrial morphogenesis, and show that in cells lacking anxA6 mitochondria are fragmented, respiration is impaired and mitochondrial membrane potential is reduced. In fibroblasts from AnxA6 −/− mice, mitochondrial Ca2+ uptake is reduced and cytosolic Ca2+ transients are elevated. These observations led us to investigate possible interactions between anxA6 and proteins with roles in mitochondrial fusion and fission. We found that anxA6 associates with Drp1 and that mitochondrial fragmentation in AnxA6 −/− fibroblasts was prevented by the Drp1 inhibitor mdivi-1. In normal cells elevation of intracellular Ca2+ disrupted the interaction between anxA6 and Drp1, displacing anxA6 to the plasma membrane and promoting mitochondrial fission. Our results suggest that anxA6 inhibits Drp1 activity, and that Ca2+-binding to anxA6 relieves this inhibition to permit Drp1-mediated mitochondrial fission.