Detection of viral RNAs causes oligomerization of mitochondrial antiviral signaling (MAVS) protein, which leads to the production of type I interferons (IFNs). Buskiewicz et al. found that MAVS oligomerization in the absence of virus may contribute to lupus disease severity. Mitochondrial reactive oxygen species (ROS) induced MAVS oligomerization and type I IFN production in uninfected cells. The MAVS C79F variant, which is associated with decreased lupus severity, did not oligomerize in response to ROS, and cells expressing this variant produced less type I IFN.