A recent study suggests that voltage‐dependent anion channel (VDAC) oligomer pores promote mitochondrial outer membrane permeabilization and allow mitochondrial DNA (mtDNA) to be released into the cytosol in live cells. It challenges the notion that only occurs in apoptotic cells via BAX/BAK macropores. Cytosolic mtDNA activates cyclic GMP–AMP synthase (cGAS)–stimulator of IFN gene (STING) pathway and triggers type I interferon (IFN) response thereafter, which ultimately causes systemic lupus erythematosus. Mechanistically, mtDNA can interact with three positively charged residues (Lys12, Arg15, and Lys20) at the N‐terminus of VDAC1, thereby strengthening VDAC1 oligomerization and facilitating mtDNA release. In addition, there are other pathways that can mediate mtDNA release, such as BAX/BAK macropores and virus‐derived pores. The mtDNA released into the cytosol also triggers type I IFN response via the generally accepted cGAS–STING–TANK‐binding kinase 1–IFN regulatory factor 3 axis. Collectively, VDAC oligomer pores provide us an attractive direction for us to understand mtDNA release‐related diseases.

中文翻译：

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VDAC低聚物毛孔：线粒体DNA释放引发的疾病机制。

一项最新研究表明，电压依赖性阴离子通道（VDAC）的低聚物孔促进了线粒体外膜的透化作用，并使线粒体DNA（mtDNA）释放到活细胞的细胞质中。它挑战仅通过BAX / BAK大孔在凋亡细胞中发生的观念。胞质mtDNA激活环状GMP-AMP合酶（cGAS）-IFN基因（STING）途径的刺激物，并随后触发I型干扰素（IFN）反应，最终导致系统性红斑狼疮。从机理上讲，mtDNA可以与VDAC1的N端的三个带正电荷的残基（Lys12，Arg15和Lys20）相互作用，从而加强VDAC1的寡聚并促进mtDNA的释放。此外，还有其他可介导mtDNA释放的途径，例如BAX / BAK大孔和病毒来源的孔。释放到细胞质中的mtDNA也通过公认的cGAS–STING–TANK结合激酶1–IFN调节因子3轴触发I型IFN反应。总体而言，VDAC低聚物孔为我们提供了一个了解mtDNA释放相关疾病的诱人方向。