TY - JOUR
T1 - Increased protein propionylation contributes to mitochondrial dysfunction in liver cells and fibroblasts, but not in myotubes
AU - Lagerwaard, Bart
AU - Pougovkina, Olga
AU - Bekebrede, Anna F
AU - Te Brinke, Heleen
AU - Wanders, Ronald J A
AU - Nieuwenhuizen, Arie G
AU - Keijer, Jaap
AU - de Boer, Vincent C J
N1 - Funding Information:
We would like to acknowledge Laura de Smalen for her help in data collection and the Gaslini Biobank in Italy for providing the propionyl‐CoA carboxylase deficient fibroblasts. This project was financed by the TIFN research program Mitochondrial Health (ALWTF.2015.5) and the Netherlands Organization for Scientific Research (NWO).
Publisher Copyright:
© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - mitochondria
KW - oxidative metabolism
KW - post-translational protein modifications
KW - propionic acidemia
KW - propionylation
UR - http://www.scopus.com/inward/record.url?scp=85089458056&partnerID=8YFLogxK
U2 - 10.1002/jimd.12296
DO - 10.1002/jimd.12296
M3 - Article
C2 - 32740932
SN - 0141-8955
VL - 44
SP - 438
EP - 449
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 2
ER -