Abstract
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.
Highlights
Post-translational protein modifications (PTMs) are an important regulatory mechanism for protein functionality and localisation
We previously showed that a state of metabolic propionic acidemia (PA) significantly induces protein propionylation.[20]
The aim of this study was to assess the role of protein propionylation in the aetiology of PA and in cultured cells
Summary
Post-translational protein modifications (PTMs) are an important regulatory mechanism for protein functionality and localisation. Protein acylation involves the covalent binding of acyl-groups to lysine residues of a protein and directly links metabolism and protein functionality.[1] For example, intermediates of metabolism, such as acetylCoA, drive protein acetylation[2] and can serve as a regulatory mechanism in fatty acid oxidation by acetylation of enzymes involved in the breakdown of fatty acids.[3]. Muscle and liver biopsies from PCC patients show defective mitochondrial respiration, suggesting that mitochondrial dysfunction contributes to the pathology.[18,19] Interestingly, it is not known how increased levels of propionyl-CoA can contribute to this. Fibroblasts derived from patients display increased protein propionylation, showing that pathological build-up of intermediates of propionyl-CoA metabolism can alter the protein acylome.[20] We hypothesised that the increased propionylation disrupts normal mitochondrial function and contributes to the mitochondrial phenotype. We use control and patient-derived fibroblasts and cultured cells to study the mitochondrial effects of increased propionylation to explore a possible role of this PTM in health and disease
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