VDAC oligomers form mitochondrial pores that release small mtDNA fragments and promote lupus-like disease
By Jeonghan Kim, Rajeev Gupta, L. Blanco, Shutong Yang, A. Shteinfer-Kuzmine, Kening Wang, Jun Zhu, H. E. Yoon, Xinghao Wang, M. Kerkhofs and 10 more. Science, 2019
644 citations recorded by the source corpus.
VDACs are MOM's ruin Mitochondrial DNA (mtDNA) is normally kept within the mitochondria. It can be released into the cytosol in response to stress and thus encounter cytosolic DNA sensors, triggering type I interferon responses. During apoptosis, mtDNA release is mediated by macropores in the mitochondrial outer membrane (MOM) created by oligomerization of the proteins BAX and BAK. Kim et al. found that during oxidative stress, mtDNA escapes instead through macropores formed by oligomerization of voltage-dependent anion channels (VDACs) (see the Perspective by Crow). In a mouse model of lupus, an inhibitor of VDAC oligomerization diminished mtDNA release and downstream signaling events. This treatment reduced lupus-like symptoms in the model, suggesting a potential therapeutic route for conditions mediated by mtDNA release. Science, this issue p. 1531; see also p. 1445 The inhibition of a mitochondrial porin’s oligomerization prevents mitochondrial DNA release and ameliorates lupus-like disease in mice. 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.
Subfields: Immunology, Molecular Biology, Rheumatology
View Paper: https://www.semanticscholar.org/paper/e10805b6c3dac107a3b160d99c0578ac0c4c9cd7
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Citations in the corpus
- Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “149,150 Indeed, the inhibition of mPTP opening with CsA reduced the cytosolic pools of mtDNA by 30% – 40%, and VDAC oligomerization inhibition with VBIT-4 reduced cytosolic mtDNA by 50 – 60%.”
- TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “These in vitro data demonstrate a mechanism by which TDP-43 can mislocalize into mitochondria, opening the mPTP and resulting in VDAC1dependent mtDNA leakage into the cytoplasm.”
- Mitochondrial DNA in inflammation and immunity (2020, positive): “Using the VDAC1 oligomerisation inhibitor VBIT-4, the authors were able to reduce lupus-like symptoms in lupus-prone mice, providing a rationale to target VDAC-mediated mtDNA release in this disease [85].”