The immune system provides essential protection from microbial infection but can damage tissue when its functions are excessive, sustained, or insufficiently regulated. In autoimmune disease, T lymphocytes and autoantibodies (antibodies directed to “self”-antigens) target the immune response to host tissue. But innate immunity, the first response to infection or cell stress, is also important in orchestrating pathologic immune responses in autoimmune diseases. The type I interferon (IFN) family of innate immune cytokines contributes to the aberrant immune functions of systemic lupus erythematosus (SLE) and several other autoimmune diseases (1). Self–nucleic acids induce type I IFN in SLE, but the mechanisms are not clear. On page 1531 of this issue, Kim et al. (2) show that pores formed by oligomerization of the mitochondrial voltage-dependent anion channel (VDAC) allow short mitochondrial DNA (mtDNA) fragments from stressed mitochondria to enter the cytosol, which may then induce type I IFN production.

In SLE, autoantibody-containing immune complexes promote tissue damage and variable symptoms that include rash, arthritis, kidney disease, and cardiovascular disease. White blood cells from SLE patients demonstrate a type I IFN “signature” characterized by increased expression of hundreds of IFN-regulated genes (1). Sustained activation of the IFN pathway supports differentiation of T follicular helper cells, development of autoantibody-producing plasma cells, and recruitment of inflammatory cells that produce tissue damage. Candidate cellular pathways that could induce type I IFN in SLE include the endosomal Toll-like receptors (TLRs), particularly TLR7, which recognizes single-stranded RNA in lupus immune complexes (3), and cytosolic sensors of DNA or RNA that engage the adapter STING (stimulator of interferon genes) (4). RNA-containing immune complexes are found in sera from many patients with SLE and have a well-established role in TLR7-dependent production of type I IFN by plasmacytoid dendritic cells, robust producers of the type I IFN-α cytokine (35). The relevance of the cytosolic pathways and their nucleic acid triggers in SLE pathogenesis is less well established.

Conditions of oxidative stress that generate mitochondrial reactive oxygen species (mROS) can cause mtDNA damage and single-stranded breaks, which can lead to mtDNA degradation. The resulting fragments might be a stimulus for type I IFN production (6). In contrast to nuclear DNA, mtDNA includes CpG sequences that are less methylated, is packaged into DNA-protein complexes (nucleoids) rather than associated with histones, and may have less robust DNA repair mechanisms. Release of mtDNA might stimulate cytosolic DNA sensors, including cyclic guanosine monophospate (GMP)–adenosine monophosphate (AMP) synthase (cGAS), and activate the downstream kinase TANK-binding kinase 1 (TBK1) and the transcription factor interferon regulatory factor 3 (IRF3) after engaging STING, an inducer of type I IFN production. mtDNA that has been modified by ROS or other cell stressors is a particularly effective inducer of type I IFN (7). Thus, mtDNA could be an initiator of SLE by providing a trigger for innate immune system activation. If mtDNA leakage persisted over time, it could amplify established autoimmunity through effects of type I IFN on T and B lymphocytes and neutrophils, inducing clinically important disease flares.


Release of mitochondrial DNA induces interferon production

Moderate amounts of environmental or endogenous stress promote mtDNA (nucleoids) to become fragmented. Interaction of these fragments with VDAC induces its oligomerization to form pores. mtDNA fragments enter the cytosol, where they activate the sensor cGAS and, in turn, STING-mediated induction of type I interferon and inflammation.




The study by Kim et al. identifies a role for mitochondrial stress in inducing oligomerization of VDAC, a molecule in the outer mitochondrial membrane that controls entry and exit of metabolites. The authors demonstrate that interaction of amino-terminal amino acids of VDAC1, one of several VDAC proteins, with mtDNA initiates pore formation. Mitochondria with increased mROS release small fragments of mtDNA into the cytosol through the VDAC pore, triggering induction of type I IFN through a signaling pathway that involves STING (see the figure).

The authors find increased VDAC oligomerization in spleen cells from a mouse model of SLE and in white blood cells from several SLE patients. Administration of an inhibitor of VDAC oligomerization, VBIT-4, to SLE mice reduced accumulation of cytosolic mtDNA, decreased expression of type I IFN-regulated genes, and abrogated features of autoimmune disease, including autoantibody production. Although inhibitors of the VDAC pore might be effective in reducing stimulatory mtDNA, the importance of the VDAC pore for transport of essential metabolites could complicate use of VDAC inhibitors as therapeutics for SLE or other disorders (8).

An important aspect of the study of Kim et al. is that the model reflects the effect of moderate levels of mitochondrial stress that do not result in cell death. Although a macropore formed by the proteins BAX (Bcl-2 associated X) and BAK (Bcl-2 homologous antagonist/killer) mediates mtDNA release to the cytosol under more extreme conditions, leading to programmed cell death (apoptosis) (9), formation of VDAC oligomers may occur under conditions of milder stress, induced by environmental factors, including microbial infection, or host factors that prime mitochondria for sensitivity to endogenous stressors.

Beyond their essential role in energy metabolism, the capacity of mitochondria to interpret external signals through modification of mtDNA and the outer mitochondrial membrane is of considerable interest. The pathogenic bacterium Streptococcus pyogenes encodes a protein that promotes transport of mtDNA to the cytosol, triggering production of type I IFN as a mechanism to modulate the immune response (10). Of relevance to mechanisms of lupus nephritis, a clinical manifestation of SLE reflecting kidney damage, a genetic variant of apolipoprotein L1 (APOL1), which is associated with increased risk of end-stage renal disease in African Americans, encodes isoforms with the capacity to form oligomers that promote opening of mitochondrial pores and induction of type I IFN (11). Thus, the study of Kim et al. suggests that pores formed by VDAC oligomers could be relevant in additional situations of mitochondrial stress.

In SLE, genetic variability and encounters with environmental stressors may determine the relative contributions of endosomal TLR signaling and sensing of cytosolic DNA in individual patients. The demonstration by Kim et al. that transfer of mtDNA to the cytosol occurs under relatively benign conditions of mitochondrial stress suggests that induction of type I IFN through sensing of mtDNA could be applicable to many patients and different environmental triggers. In light of their data, investigating the contribution of mtDNA to innate immune responses in the pathogenesis of SLE and other diseases is warranted.




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