Multicellular organisms constantly encounter biotic and abiotic stressors that threaten to disrupt their homeostasis. To counteract this, they have evolved a series of conserved defense networks which monitor organellar function and the accumulation of aberrant molecular signals. As mitochondrial dysfunction can lead to a variety of pathologies, including metabolic impairment, neurodegeneration, cardiovascular disease, cancer, and sensitivity to bacterial infections, understanding these mitochondrial surveillance pathways is crucial. Previous research in our lab established that one such pathway, the Ethanol Stress and Response Element (ESRE), was activated by a broad range of stresses, including exposure to the Gram-negative, opportunistic human pathogen . In this report we show that MDT-15 and its downstream effectors, fatty acid desaturases FAT-6 and FAT-7, were required for ESRE activation. Interestingly, supplementation with fatty acids downstream of FAT-6/FAT-7 activity, from ' PUFA pathway, rescued ESRE activation in their knockdowns. Additionally, disruption of , or its downstream effector by RNAi diminished worm survival during exposure to , indicating that these genes play a role in host defense. Notably, box C/D snoRNPs complex that we previously identified as an activator of ESRE, is required for upregulation of fatty acid metabolism under ESRE-activating conditions. Our results provide insight into a novel interplay between box C/D snoRNPs, lipids, and MDT-15/Mediator in the regulation of mitochondrial surveillance and innate immunity.