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

Biochim Biophys Acta Mol Basis Dis. 2019 Dec 1;1865(12):165538. doi: 10.1016/j.bbadis.2019.165538. Epub 2019 Aug 23.

Abstract

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.

Keywords: Methylmalonic acidemia; Propionic acidemia; Serine metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / metabolism*
  • Cells, Cultured
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Metabolome
  • Metabolomics
  • Propionic Acidemia / metabolism*
  • Proteome / metabolism
  • Proteomics
  • Serine / metabolism*

Substances

  • Proteome
  • Serine

Supplementary concepts

  • Methylmalonic acidemia