Interplay between mitochondria and diet mediates pathogen and stress resistance in Caenorhabditis elegans

Abstract

Diet is a crucial determinant of organismal biology; interactions between the host, its diet, and its microbiota are critical to determining the health of an organism. A variety of genetic and biochemical means were used to assay stress sensitivity in C. elegans reared on two standard laboratory diets: E. coli OP50, the most commonly used food for C. elegans, or E. coli HT115, which is typically used for RNAi-mediated gene knockdown. We demonstrated that the relatively subtle shift to a diet of E. coli HT115 had a dramatic impact on C. elegans’s survival after exposure to pathogenic or abiotic stresses. Interestingly, this was independent of canonical host defense pathways. Instead the change arises from improvements in mitochondrial health, likely due to alleviation of a vitamin B12 deficiency exhibited by worms reared on an E. coli OP50 diet. Increasing B12 availability, by feeding on E. coli HT115, supplementing E. coli OP50 with exogenous vitamin B12, or overexpression of the B12 transporter, improved mitochondrial homeostasis and increased resistance. Loss of the methylmalonyl-CoA mutase gene mmcm-1/MUT, which requires vitamin B12 as a cofactor, abolished these improvements, establishing a genetic basis for the E. coli OP50-incurred sensitivity. Our study forges a mechanistic link between a dietary deficiency (nutrition/microbiota) and a physiological consequence (host sensitivity), using the host-microbiota-diet framework.

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism

“…Old age metformin toxicity developed regardless of the bacterial viability and/or strain (Figure 1C and D) suggesting that late life metformin intolerance is independent of previously uncovered microbiome changes. Interestingly, the baseline survival of nematodes differed between UV killed OP50 and HT115 diets in line with recently reported dependence of nematode physiological behaviors on the bacterial source (Revtovich et al, 2019).…”

Lysosomal activity regulatesCaenorhabditis elegansmitochondrial dynamics through vitamin B12 metabolism

“…We found that wild type animals grown on E. coli OP50 had mildly increased mitochondrial fragmentation, which could be complemented by exogenous B12 supplementation ( Fig. 4B, lower panels), as has been observed (Revtovich et al, 2019). Moreover, Phsp-6::GFP was slightly induced on an E. coli OP50 diet, indicating mild mitochondrial dysfunction caused by B12 deficiency (Fig.…”

“…S13E). Mild B12 deficiency affected mitochondrial homeostasis and increased susceptibility to pathogenic infections in animals (46). However, in a drp-1/dynamin mutation background, B12 deficiency, on the contrary, improves C. elegans mitochondrial health by rebalancing mitochondrial fission-fusion events (Fig.…”

Repurposing bioactive compounds for treating multidrug-resistant pathogens

“…For example, the C. elegans experiments differed in host (glp-4 vs glp-4; sek-1) and bacterial strains (S. aureus strain MRSA131 vs S. aureus strain MW2), timing, and even the host's diets varied (E. coli strain OP50 vs E. coli strain HB101). We have previously shown that switching the diet of C. elegans between the E. coli strains OP50 and HT115 significantly changes its susceptibility to P. aeruginosa PA14 [47], perhaps a similar phenomenon exists for S. aureus. Ultimately, much more work is needed to determine the potential of CD437 to treat S. aureus.…”