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

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

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

Abstract

Mitochondrial stress releases mitochondrial DNA (mtDNA) into the cytosol, thereby triggering the type I 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.

Original languageEnglish
Pages (from-to)1531-1536
Number of pages6
JournalScience
Volume366
Issue number6472
DOIs
StatePublished - 20 Dec 2019

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