Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans

• Published in: eLife Vol. 5
• Main Authors: Watson, Emma, Olin-Sandoval, Viridiana, Hoy, Michael J, Li, Chi-Hua, Louisse, Timo, Yao, Victoria, Mori, Akihiro, Holdorf, Amy D, Troyanskaya, Olga G, Ralser, Markus, Walhout, Albertha JM
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06.07.2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; bacteria; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Candida albicans; Computational and Systems Biology; Datasets; Diet; E coli; Enzymes; Gene mapping; Genes; Genes and Chromosomes; Genomes; Genomics; Health aspects; Metabolic Engineering; Metabolic Networks and Pathways - genetics; Metabolism; Metabolites; Mimicry; Mutation; Nematodes; network rewiring; Nutrient deficiency; Observations; Oxidation; propionate; Propionates - metabolism; Propionic acid; Transcription; Vitamin B 12 Deficiency; Vitamin B12; Vitamin deficiency; computational biology; systems biology; C. elegans; bacteria; transcription; genes; chromosomes; metabolism; network rewiring; vitamin B12; human; propionate
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.17670

Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild. Inborn errors of metabolism are human genetic diseases that cause developmental delays and are usually fatal. Propionic acidemia is an inborn error of metabolism where propionate, a byproduct created during the breakdown of fat and proteins, cannot be broken down efficiently. As a result, propionate builds up to toxic levels inside cells. Most animals, including humans, use a particular enzyme pathway to get rid of propionate. This pathway needs vitamin B12 in order to work, which is obtained from food. Newborns are screened for propionic acidemia using a test that measures the levels of a molecule called 3-hydroxypropionate (3-HP) in the body. This molecule is not normally found in appreciable levels in healthy humans. However, it is not clear how 3-HP forms in individuals with propionic acidemia. In 2014, researchers showed that in worms called Caenorhabditis elegans, propionate activates many genes when vitamin B12 levels are low. This suggests that the worms may have an alternate way to break down propionate when vitamin B12 is in short supply. Now, Watson et al. – including some of the researchers involved in the 2014 work – have used a combination of genetic, computational and biochemical techniques to identify five genes that the worms use to break down propionate when vitamin B12 is not available. Furthermore, the level of 3-HP rises in worms that cannot use B12, just as is seen in humans with propionic acidemia. Thus, it appears that producing 3-HP may be an important step in an alternate pathway that does not require vitamin B12 to eliminate propionate. Having an alternate way of breaking down propionate may be essential for C. elegans worms living in the wild, which have to adapt to changing dietary conditions that may or may not provide them with vitamin B12. Further studies are now needed to describe the metabolic effects of genes turned on by propionate and repressed by vitamin B12, and to investigate how propionate alters the activity of these genes.