Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.

中文翻译：

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与 ATAD3A 突变相关的 cGAS-STING 依赖性干扰素信号增强

线粒体 DNA (mtDNA) 被认为可驱动免疫系统激活，但尚未在孟德尔线粒体疾病中证实 mtDNA 对干扰素信号传导的诱导作用。我们最初确定了两名患者，一名具有纯粹的神经表型，另一名具有在综合征背景下提示系统性硬化症的特征，并发现他们都表现出增强的干扰素刺激基因 (ISG) 在血液中的表达。我们确定每一个在ATAD3A中都含有先前描述的从头显性失活杂合突变，编码 ATPase 家族 AAA 结构域的蛋白质 3A (ATAD3A)。我们确定了另外五名ATAD3A突变的患者，并在其中四名中记录了上调的 ISG 表达和干扰素 α 蛋白。击倒THP-1 细胞中的ATAD3A导致干扰素信号传导增加，由环状 GMP-AMP 合酶 (cGAS) 和干扰素基因刺激物 (STING) 介导。增强的干扰素信号在 THP-1 细胞和耗尽 mtDNA 的患者成纤维细胞中被消除。因此，线粒体膜蛋白 ATAD3A 的突变定义了一种新型 I 型干扰素病。