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.

哺乳动物线粒体 DNA 的双向转录产生重叠的转录本，这些转录本能够形成双链 RNA （dsRNA） 结构。线粒体 dsRNA 释放到胞质溶胶中会激活 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。更好地了解该过程对于这种防御机制的治疗应用和治疗同源人类疾病至关重要。除了输出 dsRNA 外，线粒体还输出和输出各种非编码 RNA。然而，关于这些 RNA 如何跨线粒体膜运输知之甚少。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） 在线粒体内膜中作为哺乳动物 RNA 转位子发挥作用，与其 ADP/ATP 转位酶活性无关。我们还表明，线粒体 dsRNA 通过 ANT2 外排会触发先天免疫。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了一种潜在的治疗方法。