ANT2 functions as a translocon for mitochondrial cross-membrane translocation of RNAs

IF 28.1 1区 生物学 Q1 CELL BIOLOGY Cell Research Pub Date : 2024-05-29 DOI:10.1038/s41422-024-00978-5
Pengcheng Wang, Lixiao Zhang, Siyi Chen, Renjian Li, Peipei Liu, Xiang Li, Hongdi Luo, Yujia Huo, Zhirong Zhang, Yiqi Cai, Xu Liu, Jinliang Huang, Guangkeng Zhou, Zhe Sun, Shanwei Ding, Jiahao Shi, Zizhuo Zhou, Ruoxi Yuan, Liang Liu, Sipeng Wu, Geng Wang
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Abstract

Bidirectional transcription of mammalian mitochondrial DNA generates overlapping transcripts that are capable of forming double-stranded RNA (dsRNA) structures. Release of mitochondrial dsRNA into the cytosol activates the dsRNA-sensing immune signaling, which is a defense mechanism against microbial and viral attack and possibly cancer, but could cause autoimmune diseases when unchecked. A better understanding of the process is vital in therapeutic application of this defense mechanism and treatment of cognate human diseases. In addition to exporting dsRNAs, mitochondria also export and import a variety of non-coding RNAs. However, little is known about how these RNAs are transported across mitochondrial membranes. Here we provide direct evidence showing that adenine nucleotide translocase-2 (ANT2) functions as a mammalian RNA translocon in the mitochondrial inner membrane, independent of its ADP/ATP translocase activity. We also show that mitochondrial dsRNA efflux through ANT2 triggers innate immunity. Inhibiting this process alleviates inflammation in vivo, providing a potential therapeutic approach for treating autoimmune diseases.

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ANT2 作为线粒体跨膜转运 RNA 的转运体。
哺乳动物线粒体 DNA 的双向转录产生的重叠转录本能够形成双链 RNA(dsRNA)结构。线粒体 dsRNA 释放到细胞质中会激活 dsRNA 感应免疫信号,这是一种抵御微生物和病毒攻击以及可能的癌症的防御机制,但如果不加以控制,可能会导致自身免疫性疾病。更好地了解这一过程对于这种防御机制的治疗应用和人类同类疾病的治疗至关重要。除了输出 dsRNA 外,线粒体还输出和输入各种非编码 RNA。然而,人们对这些 RNA 如何跨线粒体膜运输知之甚少。在这里,我们提供的直接证据表明,腺嘌呤核苷酸转位酶-2(ANT2)在线粒体内膜上发挥着哺乳动物 RNA 转位酶的功能,而与其 ADP/ATP 转位酶活性无关。我们还发现,线粒体 dsRNA 通过 ANT2 外流会触发先天性免疫。抑制这一过程可以缓解体内炎症,为治疗自身免疫性疾病提供了一种潜在的治疗方法。
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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