miR-34a/ATG9A/TFEB Signaling Modulates Autophagy in Cochlear Hair Cells and Correlates with Age-related Hearing Loss
miR-34a/ATG9A/TFEB Signaling Modulates Autophagy in Cochlear Hair Cells and Correlates with Age-related Hearing Loss
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miR-34a/ATG9A/TFEB 信号传导调节耳蜗毛细胞的自噬并与年龄相关的听力损失相关
DOI：
10.1016/j.neuroscience.2022.03.033
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发表时间：
2022-03
期刊：
影响因子：
3.3
通讯作者：
Zheng Yiqing
中科院分区：
文献类型：
--
作者：
Xiong Hao;Pang Jiaqi;Min Xin;Ye Yongyi;Lai Lan;Zheng Yiqing
我们以前的研究表明，miR-34 a抑制老化耳蜗中的自噬，这与耳蜗毛细胞损失和年龄相关性听力损失（阿勒）相关。然而，耳蜗中miR-34 a调控自噬的潜在机制仍不清楚。在这里，我们表明，核转位的转录因子EB（TFEB），自噬的主调节器，在HEI-OC 1细胞中的miR-34 a的调节。此外，ATG 9A是miR-34 a的主要靶点之一，显示与TFEB相互作用，从而促进其在HEI-OC 1细胞中的核转位。雷帕霉素解除了miR-34 a/ATG 9A激活诱导的TFEB核转位的抑制，恢复了自噬通量，从而阻止了HEI-OC 1细胞死亡。长期补充雷帕霉素减弱了C57 BL/6小鼠的外毛细胞（OHC）和内毛细胞突触带，并延迟了阿勒。最重要的是，雷帕霉素部分恢复了TFEB在老化耳蜗OHC中的核定位和自噬通量。这些发现为通过miR-34 a/ATG 9a/TFEB调节自噬来保护免受阿勒开辟了新的途径。
Our previous studies revealed that miR-34a suppresses autophagy in the ageing cochlea, which correlates with cochlear hair cell loss and age-related hearing loss (AHL). However, the mechanisms underlying miR-34a regulation of autophagy in the cochlea remain unclear. Here, we show that nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy, was regulated by miR-34a in HEI-OC1 cells. Moreover, ATG9A, one of the main targets of miR-34a, was shown to interact with TFEB and thus promote its nuclear translocation in HEI-OC1 cells. Rapamycin rescued the inhibition of TFEB nuclear translocation induced by miR-34a/ATG9A activation, restored autophagic flux and consequently prevented HEI-OC1 cell death. Long-term supplementation with rapamycin attenuated outer hair cells (OHCs) and inner hair cell synaptic ribbons, and delayed AHL in C57BL/6 mice. Most importantly, rapamycin partially restored TFEB’s nuclear localization and autophagic flux in OHCs of the ageing cochlea. These findings open new avenues for protection against AHL through miR-34a/ATG9a/TFEB modulation of autophagy.
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影响因子：
11.1
作者：
Pastore, Nunzia;Blomenkamp, Keith;Annunziata, Fabio;Piccolo, Pasquale;Mithbaokar, Pratibha;Sepe, Rosa Maria;Vetrini, Francesco;Palmer, Donna;Ng, Philip;Polishchuk, Elena;Iacobacci, Simona;Polishchuk, Roman;Teckman, Jeffrey;Ballabio, Andrea;Brunetti-Pierri, Nicola
通讯作者：
Brunetti-Pierri, Nicola
影响因子：
5
作者：
Cheng, Xinru;Xu, Qianya;Zhang, Qian
通讯作者：
Zhang, Qian
影响因子：
--
作者：
Yang, Jurong;Chen, Dapeng;Chen, Xiangmei
通讯作者：
Chen, Xiangmei
影响因子：
17.1
作者：
Tsunemi T;Ashe TD;Morrison BE;Soriano KR;Au J;Roque RA;Lazarowski ER;Damian VA;Masliah E;La Spada AR
通讯作者：
La Spada AR
影响因子：
11.8
作者：
Medina, Diego L.;Fraldi, Alessandro;Bouche, Valentina;Annunziata, Fabio;Mansueto, Gelsomina;Spampanato, Carmine;Puri, Claudia;Pignata, Antonella;Martina, Jose A.;Sardiello, Marco;Palmieri, Michela;Polishchuk, Roman;Puertollano, Rosa;Ballabio, Andrea
通讯作者：
Ballabio, Andrea