New insights into the pathophysiology of methylmalonic acidemia

J Inherit Metab Dis. 2023 May;46(3):436-449. doi: 10.1002/jimd.12617.


Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment options are limited and non-curative as the underlying causative molecular mechanisms remain unknown. While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA and potentially reduced function of all three indicates aberrant acylation may require clinical intervention. Therefore, targeting posttranslational modifications may represent a new therapeutic approach to treat MMA and related organic acidemias.

Keywords: MMA; PTM; methylmalonyl-CoA mutase; organic acidemia; sirtuin.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Metabolism, Inborn Errors* / therapy
  • Humans
  • Methylmalonic Acid
  • Methylmalonyl-CoA Mutase / metabolism
  • Mitochondria / metabolism
  • Propionic Acidemia*


  • Methylmalonyl-CoA Mutase
  • Methylmalonic Acid

Supplementary concepts

  • Methylmalonic acidemia