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

Abstract

Host-pathogen conflicts leave genetic signatures of variation in homologous host genes. 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 fundamental biological processes.

Alternative splicing liberates a cryptic cytoplasmic isoform of mitochondrial MECR that antagonizes influenza virus

“…Mitochondria are a major subcellular location where host-pathogen conflicts play out: cellular IFN pathways use the mitochondrial membrane to assemble signaling hubs containing MAVS; mitochondrial nucleic acids can be unshielded to trigger the type-I IFN response, and miRNAs that can regulate IFN stimulated genes are embedded in mitochondrial genes (Dhir et al, 2018; Hou et al, 2011; Refolo et al, 2020; Sorouri et al, 2020). Knockdown of MECR in A549 MAVS, RIG-I, or PKR knockout cells still alleviates its antiviral activity ( Supp.…”