| Literature DB >> 31857488 |
Jeonghan Kim1, Rajeev Gupta2, Luz P Blanco3, Shutong Yang1, Anna Shteinfer-Kuzmine2, Kening Wang4, Jun Zhu5,6, Hee Eun Yoon1, Xinghao Wang3, Martijn Kerkhofs7, Hyeog Kang1, Alexandra L Brown1, Sung-Jun Park1, Xihui Xu1, Eddy Zandee van Rilland1, Myung K Kim1, Jeffrey I Cohen4, Mariana J Kaplan3, Varda Shoshan-Barmatz2, Jay H Chung8.
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.Entities:
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Year: 2019 PMID： 31857488 PMCID： PMC8325171 DOI： 10.1126/science.aav4011
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728