Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.
Integration of FUNDC1-associated mitochondrial protein import and mitochondrial quality control contributes to TDP-43 degradation.
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DOI：
10.1038/s41419-023-06261-6
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发表时间：
2023-11-11
影响因子：
9
通讯作者：
Zhu, Li
中科院分区：
文献类型：
--
作者：
Ma, Jinfa;Liu, Lei;Song, Lu;Liu, Jianghong;Yang, Lingyao;Chen, Quan;Wu, Jane Y.;Zhu, Li
虽然TDP-43蛋白质可以转位到线粒体中并导致TDP-43蛋白质病中的线粒体损伤，但是关于TDP-43如何被输入到线粒体中的知之甚少。此外，线粒体损伤是由TDP-43的线粒体错误定位引起的，还是由线粒体介导的TDP-43降解的副作用引起的，仍有待研究。在这里，我们的生物信息学分析显示，线粒体自噬受体基因FUNDC 1与TDP-43共表达，并且TDP-43和FUNDC 1的表达均与诊断为TDP-43蛋白质病的患者脑样本中线粒体蛋白输入途径相关的基因相关。FUNDC 1可能通过促进TDP-43-TOM 70和DNAJA 2-TOM 70相互作用促进TDP-43的线粒体易位，这在细胞实验中不依赖于FUNDC 1的LC 3相互作用区域。在TDP-43蛋白质病的转基因果蝇模型中，过表达FUNDC 1增强TDP-43诱导的线粒体损伤，而下调FUNDC 1逆转TDP-43诱导的线粒体损伤。FUNDC 1不仅通过调节线粒体TDP-43的输入，还通过增加LONP 1水平和激活线粒体自噬来调节线粒体介导的TDP-43降解，线粒体自噬在胞质TDP-43清除中起重要作用。总之，这项研究不仅揭示了线粒体TDP-43输入的机制，而且还揭示了线粒体在调节TDP-43稳态中发挥的积极作用。
Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.
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