Box C/D snoRNPs and MDT-15/MED15 regulate mitochondrial surveillance and mitophagy via fatty acid metabolism

In response to constant homeostatic threats, organisms have developed complex regulatory networks to monitor cellular functions and restore normal function. Here, we identify MDT-15 and its effectors, the fatty acid desaturases FAT-5, FAT-6, and FAT-7, as activators of the Ethanol and Stress Response (ESRE) mitochondrial surveillance pathway. Our data show that box C/D snoRNPs, which were previously linked to ESRE activation, also regulate FAT-6 and FAT-7 protein levels. Notably, knockdown of mdt-15 or fib-1, a component of the box C/D snoRNP complex, increased accumulation of the mitophagic activator PINK-1, the first step in licensing mitophagy, suggesting a relationship between ESRE surveillance and mitophagic activation. Our results show that both MDT-15 and FAT-6 are required for host defense against liquid-based Pseudomonas aeruginosa pathogenesis, linking this mitochondrial surveillance network to resistance against acute infection. Supplementation with downstream unsaturated fatty acid products of FAT-6 and FAT-7 enhanced ESRE and mitophagic activation, but did not affect the mitochondrial unfolded protein response (UPR^mt) pathway. Since fatty acids activated ESRE and PINK-1 in wild-type and mutant genetic backgrounds, they are likely to act via a mechanism independent of FAT-6 and FAT-7 function. Our results provide insight into a novel interplay between box C/D snoRNPs, MDT-15, and fatty acids in the regulation of mitochondrial surveillance, mitophagy, and host defense.