When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)—a protein that binds mitochondrial DNA (mtDNA)—helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM’s LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

当细胞受到压力时，产生能量的线粒体中的 DNA 如果不被清除，就会泄漏并引发炎症免疫反应。细胞采用一种称为自噬的质量控制系统来专门降解受损的成分。我们发现线粒体转录因子 A (TFAM)——一种结合线粒体 DNA (mtDNA) 的蛋白质——通过自溶酶体途径（我们称之为类核吞噬）与自噬蛋白 LC3 相互作用，有助于消除泄漏的 mtDNA。 TFAM 包含一个称为 LC3 相互作用区 (LIR) 基序的分子邮政编码，可实现这种结合。虽然突变TFAM的LIR基序并没有影响其正常的线粒体功能，但更多的线粒体DNA在细胞质中积累，激活炎症信号通路。因此，TFAM 介导自噬清除泄漏的 mtDNA，以限制炎症。识别这种机制有助于理解细胞如何利用自噬机制来选择性地靶向和降解炎症 mtDNA。这些发现可以为涉及线粒体损伤和炎症的疾病的研究提供信息。