PUBLICATION
Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish
- Authors
- Zhou, W.H., Luo, Y., Li, R.X., Degrace, P., Jourdan, T., Qiao, F., Chen, L.Q., Zhang, M.L., Du, Z.Y.
- ID
- ZDB-PUB-230904-53
- Date
- 2023
- Source
- The Journal of biological chemistry 299(10): 105220 (Journal)
- Registered Authors
- Du, Zhen-Yu, Qiao, Fang, Zhang, Mei-Ling
- Keywords
- Gcn5, Raptor, acetyl-CoA, mTORC1, mitochondrial FAO inhibition
- MeSH Terms
- none
- PubMed
- 37660921 Full text @ J. Biol. Chem.
Citation
Zhou, W.H., Luo, Y., Li, R.X., Degrace, P., Jourdan, T., Qiao, F., Chen, L.Q., Zhang, M.L., Du, Z.Y. (2023) Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish. The Journal of biological chemistry. 299(10):105220.
Abstract
Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mTORC1 activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (Mildronate or Etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through Gcn5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase Gcn5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylases HDAC class II and identified HDAC7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping