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.