PT  - JOURNAL ARTICLE
AU  - Mahsa Sorouri
AU  - Tyron Chang
AU  - Palmy Jesudhasan
AU  - Chelsea Pinkham
AU  - Nels C. Elde
AU  - Dustin C. Hancks
TI  - MISTR: A conserved <span class="underline">MI</span>tochondrial <span class="underline">ST</span>ress <span class="underline">R</span>esponse network revealed by signatures of evolutionary conflict
AID  - 10.1101/2020.01.25.919811
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.25.919811
4099  - http://biorxiv.org/content/early/2020/01/26/2020.01.25.919811.short
4100  - http://biorxiv.org/content/early/2020/01/26/2020.01.25.919811.full
AB  - 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.