Increased protein propionylation contributes to mitochondrial dysfunction in liver cells and fibroblasts, but not in myotubes

Bart Lagerwaard, Olga Pougovkina, Anna F. Bekebrede, Heleen te Brinke, Ronald J.A. Wanders, Arie G. Nieuwenhuizen, Jaap Keijer, Vincent C.J. de Boer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


Post-translational protein modifications derived from metabolic intermediates, such as acyl-CoAs, have been shown to regulate mitochondrial function. Patients with a genetic defect in the propionyl-CoA carboxylase (PCC) gene clinically present symptoms related to mitochondrial disorders and are characterised by decreased mitochondrial respiration. Since propionyl-CoA accumulates in PCC deficient patients and protein propionylation can be driven by the level of propionyl-CoA, we hypothesised that protein propionylation could play a role in the pathology of the disease. Indeed, we identified increased protein propionylation due to pathologic propionyl-CoA accumulation in patient-derived fibroblasts and this was accompanied by defective mitochondrial respiration, as was shown by a decrease in complex I-driven respiration. To mimic pathological protein propionylation levels, we exposed cultured fibroblasts, Fao liver cells and C2C12 muscle myotubes to propionate levels that are typically found in these patients. This induced a global increase in protein propionylation and histone protein propionylation and was also accompanied by a decrease in mitochondrial respiration in liver and fibroblasts. However, in C2C12 myotubes propionate exposure did not decrease mitochondrial respiration, possibly due to differences in propionyl-CoA metabolism as compared to the liver. Therefore, protein propionylation could contribute to the pathology in these patients, especially in the liver, and could therefore be an interesting target to pursue in the treatment of this metabolic disease.

Original languageEnglish
Pages (from-to)438-449
Number of pages12
JournalJournal of Inherited Metabolic Disease
Issue number2
Early online date2 Aug 2020
Publication statusPublished - 2021


  • mitochondria
  • oxidative metabolism
  • post-translational protein modifications
  • propionic acidemia
  • propionylation


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