Mediator subunit MDT-15 promotes expression of propionic acid breakdown genes to prevent embryonic lethality in Caenorhabditis elegans

Abstract

The micronutrient vitamin B12 is an essential cofactor for two enzymes: methionine synthase, which plays a key role in the one-carbon cycle; and methylmalonyl-CoA mutase, an enzyme in a pathway that breaks down branched-chain amino acids and odd-chain fatty acids. A second, vitamin B12-independent pathway that degrades propionic acid was recently described in Caenorhabditis elegans, the propionate shunt pathway. Activation of five shunt pathway genes in response to low vitamin B12 availability or high propionic acid levels is accomplished by a transcriptional regulatory mechanism involving two nuclear hormone receptors, NHR-10 and NHR-68. Here, we report that the C. elegans Mediator subunit mdt-15 is also essential for the activation of the propionate shunt pathway genes, likely by acting as a transcriptional coregulator for NHR-10. C. elegans mdt-15 mutants fed with a low vitamin B12 diet have transcriptomes resembling those of wild-type worms fed with a high vitamin B12 diet, with low expression of the shunt genes. Phenotypically, the embryonic lethality of mdt-15 mutants is specifically rescued by diets high in vitamin B12, but not by dietary polyunsaturated fatty acids, which rescue many other phenotypes of the mdt-15 mutants. Finally, NHR-10 binds to MDT-15 in yeast two-hybrid assays, and the transcriptomes of nhr-10 mutants share overlap with those of mdt-15 mutants. Our data show that MDT-15 is a key coregulator for an NHR regulating propionic acid detoxification, adding to roles played by NHR:MDT-15 partnerships in metabolic regulation and pinpointing vitamin B12 availability as a requirement for mdt-15 dependent embryonic development.

Eukaryotic Elongation Factor 2 Kinase EFK-1/eEF2K promotes starvation resistance by preventing oxidative damage inC. elegans

“…Differential expression analysis was performed as described above. Venn diagrams of gene set overlaps and associated p-value was generated as described (90).…”

Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans

“…NHR-64, -66, and -80, function in lipid metabolism, and NHR-86 functions in lipid storage ( Brock et al, 2006 ; Arda et al, 2010 ; Liang et al, 2010 ; Pathare et al, 2012 ). NHR-10, -68, and -114 function in vitamin B12-dependent metabolic pathways for the methionine/S-adenosylmethionine (Met/SAM) cycle and propionate breakdown ( Gracida and Eckmann, 2013 ; Bulcha et al, 2019 ; Giese et al, 2020 ; Qin et al, 2022 ; Goh et al, 2023 ). Several NHRs are involved in pathogen defence, including NHR-14 and -86 in the response to Pseudomonas aeruginosa ( Ward et al, 2014 ; Peterson et al, 2019 ; Rajan et al, 2019 ; Peterson et al, 2023 ), NHR-45 and -156 in the response to the mold Penicillium brevicompactum ( Wallace et al, 2021 ), and NHR-42 after infection with Staphylococcus aureus ( Goswamy et al, 2023 ).…”