MISTR: A conserved MItochondrial STress Response network revealed by signatures of evolutionary conflict

Abstract While the identities of many interferon-stimulated genes (ISGs) are established, the functions of the majority of these gene products as well as their relationship with other cellular factors are unknown. To drive functional characterization, we sought to identify ISGs with genetic hallmarks indicative of conflicts with pathogens and common to key host defense factors: 1) rapid evolution and 2) viral homolog. Using these “molecular scars” as a guide, we discovered a vertebrate-specific MItochondrial STress Response circuit (MISTR). MISTR proteins are associated with electron transport chain factors and activated by stress signals such as interferon-gamma and hypoxia. Upon stress, ultraconserved miRNAs downregulate MISTR1 followed by replacement with paralogs MISTR AntiViral (MISTRAV) or MISTR Hypoxia (MISTRH), depending on the insult. While cells lacking MISTR1 are more sensitive to apoptotic triggers, cells lacking MISTRAV or expressing the poxvirus-encoded vMISTRAV exhibit resistance to the same insults. Rapid evolution signatures across primate genomes for MISTR1 and MISTRAV indicate ancient and ongoing conflicts with pathogens. MISTR proteins are also found in plants, yeasts, and an algal virus indicating ancient origins and suggesting diverse means of altering mitochondrial function under stress. The discovery of MISTR circuitry highlights the use of evolution-guided studies to reveal not only new dimensions of innate defenses but also fundamental biological processes.