美国国家心肺血液研究所Jay H. Chung研究团队的最新研究发现，VDAC低聚物形成线粒体孔以释放线粒体DNA（mtDNA）片段并促进狼疮样疾病发生。该研究于2019年12月20日发表于国际一流学术期刊《科学》。

研究人员发现氧化应激的线粒体通过线粒体外膜中的电压依赖性阴离子通道（VDAC）低聚物形成的孔释放短的mtDNA片段。此外，VDAC1的N末端结构域中带正电荷的残基与mtDNA相互作用，从而促进VDAC1的低聚。在系统性红斑狼疮小鼠模型中，VDAC低聚抑制剂VBIT-4降低了mtDNA释放、IFN信号传导、嗜中性白细胞胞外陷阱和疾病严重性。因此，抑制VDAC低聚是与mtDNA释放相关的疾病的潜在治疗方法。

研究人员表示，线粒体应激将mtDNA释放到细胞质中，从而触发了I型干扰素（IFN）反应。线粒体外膜通透性是mtDNA释放所必需的，这已在凋亡细胞中进行了广泛研究，但对其在活细胞中的作用知之甚少。

附：英文原文

Title: VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease

Author: Jeonghan Kim, Rajeev Gupta, Luz P. Blanco, Shutong Yang, Anna Shteinfer-Kuzmine, Kening Wang, Jun Zhu, Hee Eun Yoon, Xinghao Wang, Martijn Kerkhofs, Hyeog Kang, Alexandra L. Brown, Sung-Jun Park, Xihui Xu, Eddy Zandee van Rilland, Myung K. Kim, Jeffrey I. Cohen, Mariana J. Kaplan, Varda Shoshan-Barmatz, Jay H. Chung

Issue&Volume: 2019/12/20

Abstract: Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type Ι interferon (IFN) response. Mitochondrial outer membrane permeabilization, which is required for mtDNA release, has been extensively studied in apoptotic cells, but little is known about its role in live cells. We found that oxidatively stressed mitochondria release short mtDNA fragments via pores formed by the voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane. Furthermore, the positively charged residues in the N-terminal domain of VDAC1 interact with mtDNA, promoting VDAC1 oligomerization. The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release.

DOI: 10.1126/science.aav4011

Source:

https://science.sciencemag.org/content/366/6472/1531