All living organisms exist in a precarious state of homeostasis that requires constant maintenance. A wide variety of stresses, including hypoxia, heat, and infection by pathogens perpetually threaten to imbalance this state. Organisms use a battery of defenses to mitigate damage and restore normal function. In a pyoverdine-dependent Caenorhabditis elegans-Pseudomonas aeruginosa assay, C. elegans’ defense response utilizes the phylogenetically conserved ESRE (Ethanol and Stress Response Element) network, which has previously been shown to mitigate damage from a variety of abiotic stresses. It is intriguing that this network is involved in innate immunity; it indicates that host innate immune responses overlap with responses to abiotic stresses. I further investigated the ESRE defense network following exposure to P. aeruginosa and showed that mitochondrial damage leads to ESRE activation both in C. elegans and in mammals. Mitochondrial dysfunction contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Mitochondrial status is actively surveilled by several different systems to ensure the preservation of cellular viability. I characterized the ESRE pathway, a novel mitochondrial surveillance system, and showed that it is robustly activated in response to increased superoxide radical. This differentiates ESRE from other existing mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt) that monitors disruption of mitochondrial protein import and the mitochondrial MAPK (MAPKmt) pathway that responds to mitochondrial bioenergetic disruption. I also observed multiple interactions between the ESRE, UPRmt, and MAPKmt pathways. Understanding mitochondrial surveillance and the interplay that occurs among these pathways is crucial for the advancement and understanding of cell biology. Considering that the ESRE motif and its role in response to mitochondrial damage is conserved in humans, modulation of mitochondrial pathways could confer resistance to stress and improve health span, leading to a direct benefit to human health.