Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans
Emma Watson,
Viridiana Olin-Sandoval,
Michael J Hoy,
Chi-Hua Li,
Timo Louisse,
Victoria Yao,
Akihiro Mori,
Amy D Holdorf,
Olga G Troyanskaya,
Markus Ralser,
Albertha JM Walhout
Affiliations
Emma Watson
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Viridiana Olin-Sandoval
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Michael J Hoy
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Chi-Hua Li
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Timo Louisse
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Department of Computer Science, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
Akihiro Mori
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Amy D Holdorf
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Olga G Troyanskaya
Department of Computer Science, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States; Simons Center for Data Analysis, Simons Foundation, New York, United States
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom
Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
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.
