Mitochondria and Melanosomes Establish Physical Contacts Modulated by Mfn2 and Involved in Organelle Biogenesis
Mitochondria and Melanosomes Establish Physical Contacts Modulated by Mfn2 and Involved in Organelle Biogenesis
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DOI：
10.1016/j.cub.2014.01.007
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发表时间：
2014-02-17
期刊：
影响因子：
9.2
通讯作者：
Schiaffino, Maria Vittoria
中科院分区：
文献类型：
--
作者：
Daniele, Tiziana;Hurbain, Ilse;Schiaffino, Maria Vittoria
背景：为了有效地向高能量需求位点提供ATP并精细地调节钙信号，线粒体调整了它们在细胞内的代谢、形状和分布，包括相对于其他细胞器的相对定位。然而，线粒体和分泌/内吞途径之间的物理接触迄今为止仅通过结构和功能上的细胞器间连接在内质网中得到证实。结果：在这里，我们通过电子断层扫描显示，线粒体通过类似于连接线粒体和内质网的蛋白系索的纤维桥，物理接触黑色素小体，色素细胞的专门溶酶体相关细胞器。连接内质网和线粒体的Mitofusin (Mfn) 2，也特异定位于黑素体-线粒体的接触，其敲除显著减少了细胞器间的连接。接触与黑素形成过程有关，这一事实表明，在异常黑素形成模型中，接触减少，而在核周区域发生黑素体生物发生时，接触增加，当接触受到OA1（一种与眼白化病和细胞器发生有关的G蛋白偶联受体）的积极刺激时，接触增加。一致地，Mfn2敲低阻止OA1激活黑素形成，药理抑制线粒体ATP合成严重减少接触形成，损害黑素小体的生物发生，特别是通过影响显示接触频率最高的发育细胞器。总之，我们的研究结果揭示了线粒体与分泌/内吞途径之间存在前所未有的物理和功能联系，这种联系超越了er -线粒体联系，并且在空间和时间上与分泌细胞器的生物发生有关。
Background: To efficiently supply ATP to sites of high-energy demand and finely regulate calcium signaling, mitochondria adapt their metabolism, shape, and distribution within the cells, including relative positioning with respect to other organelles. However, physical contacts between mitochondria and the secretory/endocytic pathway have been demonstrated so far only with the ER, through structural and functional interorganellar connections.Results: Here we show by electron tomography that mitochondria physically contact melanosomes, specialized lysosome-related organelles of pigment cells, through fibrillar bridges resembling the protein tethers linking mitochondria and the ER. Mitofusin (Mfn) 2, which bridges ER to mitochondria, specifically localizes also to melanosome-mitochondrion contacts, and its knockdown significantly reduces the interorganellar connections. Contacts are associated to the melanogenesis process, as indicated by the fact that they are reduced in a model of aberrant melanogenesis whereas they are enhanced both where melanosome biogenesis takes place in the perinuclear area and when it is actively stimulated by OA1, a G protein-coupled receptor implicated in ocular albinism and organellogenesis. Consistently, Mfn2 knockdown prevents melanogenesis activation by OA1, and the pharmacological inhibition of mitochondrial ATP synthesis severely reduces contact formation and impairs melanosome biogenesis, by affecting in particular the developing organelles showing the highest frequency of contacts.Conclusions: Altogether, our findings reveal the presence of an unprecedented physical and functional connection between mitochondria and the secretory/endocytic pathway that goes beyond the ER-mitochondria linkage and is spatially and timely associated to secretory organelle biogenesis.