Multi-omics studies in cellular models of methylmalonic acidemia and propionic acidemia reveal dysregulation of serine metabolism

Arianna Franca Anzmann, Sneha Pinto, Veronica Busa, James Carlson, Susan McRitchie, Susan Sumner, Akhilesh Pandey, Hilary J. Vernon

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are related disorders of mitochondrial propionate metabolism, caused by defects in methylmalonyl-CoA mutase (MUT) and propionyl-CoA carboxylase (PCC), respectively. These biochemical defects lead to a complex cascade of downstream metabolic abnormalities, and identification of these abnormal pathways has important implications for understanding disease pathophysiology. Using a multi-omics approach in cellular models of MMA and PA, we identified serine and thiol metabolism as important areas of metabolic dysregulation. Methods: We performed global proteomic analysis of fibroblasts and untargeted metabolomics analysis of plasma from individuals with MMA to identify novel pathways of dysfunction. We probed these novel pathways in CRISPR-edited, MUT and PCCA null HEK293 cell lines via targeted metabolomics, gene expression analysis, and flux metabolomics tracing utilization of 13C-glucose. Results: Proteomic analysis of fibroblasts identified upregulation of multiple proteins involved in serine synthesis and thiol metabolism including: phosphoserine amino transferase (PSAT1), cystathionine beta synthase (CBS), and mercaptopyruvate sulfurtransferase (MPST). Metabolomics analysis of plasma revealed significantly increased levels of cystathionine and glutathione, central metabolites in thiol metabolism. CRISPR-edited MUT and PCCA HEK293 cells recapitulate primary defects of MMA and PA and have upregulation of transcripts associated with serine and thiol metabolism including PSAT1. 13C-glucose flux metabolomics in MUT and PCCA null HEK293 cells identified increases in serine de novo biosynthesis, serine transport, and abnormal downstream TCA cycle utilization. Conclusion: We identified abnormal serine metabolism as a novel area of cellular dysfunction in MMA and PA, thus introducing a potential new target for therapeutic investigation.

Original languageEnglish (US)
Article number165538
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number12
StatePublished - Dec 1 2019


  • Methylmalonic acidemia
  • Propionic acidemia
  • Serine metabolism

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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