Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homotypic or heterotypic complexes.
Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homotypic or heterotypic complexes.
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DOI：
10.1016/j.jbc.2022.102825
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Hu, Ying
中科院分区：
文献类型：
--
作者：
Wang, Xingwen;Zhang, Yi;Lin, Qingyu;Zhao, Kunming;Zhu, Dantong;Hu, Ying
长链非编码RNA（lncRNA）在多种生物学过程中发挥着重要作用。线粒体动力学，包括裂变和融合的连续循环，是正常工作的健康线粒体所必需的。尽管长期认识到其在细胞命运控制中的重要性，但线粒体融合的机制尚未完全理解，特别是关于lncRNA的参与。在这里，我们发现lncRNA HITT（HIF-1α翻译水平抑制剂）可以特异性定位于线粒体。表达较高水平HITT的细胞含有片段化的线粒体。相反，我们表明，HITT敲低细胞有更多的管状线粒体比存在于对照细胞。从机制上讲，我们通过体外RNA下拉和UV交联RNA-IP测定证明HITT直接结合线粒体融合素-2（MFN 2），这是介导线粒体外膜融合的核心组分。在这样做时，我们发现HITT干扰MFN 2同型或异型复合物的形成，减弱线粒体融合。在应激条件下，如紫外线辐射，我们还显示HITT稳定性增加作为MiR-205下调的结果，抑制MFN 2介导的融合并导致细胞凋亡。总的来说，我们的数据提供了重要的见解细胞器（线粒体）特异性居民lncRNA在调节线粒体融合的作用，也揭示了这样的机制如何控制细胞的敏感性紫外线辐射诱导的细胞凋亡。
Long noncoding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level) can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP assays. In doing so, we found HITT disturbs MFN2 homotypic or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.
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DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
影响因子：
21.3
作者：
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影响因子：
10.5
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通讯作者：
Gorospe M
DOI：
10.1038/nrm.2017.104
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
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通讯作者：
Khavari PA
影响因子：
8
作者：
Li, J.;Huang, Q.;Xing, J.
通讯作者：
Xing, J.