哺乳动物线粒体 DNA 的双向转录产生重叠的转录本，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，这是一种针对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。更好地理解这一过程对于这种防御机制的治疗应用和相关人类疾病的治疗至关重要。除了输出 dsRNA 之外，线粒体还输出和输入多种非编码 RNA。然而，人们对这些 RNA 如何跨线粒体膜转运知之甚少。在这里，我们提供了直接证据，表明腺嘌呤核苷酸转位酶-2 (ANT2) 在线粒体内膜中充当哺乳动物 RNA 转位子，与其 ADP/ATP 转位酶活性无关。我们还表明，线粒体 dsRNA 通过 ANT2 流出会触发先天免疫。抑制这一过程可减轻体内炎症，为治疗自身免疫性疾病提供潜在的治疗方法。© 2024。作者获得中国科学院分子细胞科学卓越中心的独家许可。

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.© 2024. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.