Journal
JOURNAL OF PROTEOME RESEARCH
Volume 18, Issue 8, Pages 3142-3155Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.9b00239
Keywords
ATP synthase; glycolysis; mitochondrial ROS; mTORC1; prolyl hydroxylases; SILAC
Categories
Funding
- MINECO, Spain [SAF2013-41945-R, SAF2016-75916-R]
- Fundacion Ramon Areces, Spain
- CIBERER-ISCIII, Spain
- [PT17/0019]
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The role played by protein turnover in metabolic reprogramming is unknown. Herein, using a SILAC approach, we have studied the changes in the half-life of 266 proteins of energy metabolism and of translation during the metabolic switch induced by the prolyl hydroxylases inhibitor dimethyloxalylglycine (DMOG). DMOG induces HIF-1 alpha expression and triggers the activation of glycolysis and the concurrent inhibition of mitochondrial respiration in colon cancer cells. Changes in the activity of energy provision pathways correlated with increased turnover rates of glycolytic enzymes and the stabilization of mitochondrial proteins. Moreover, reprogramming also stabilized the proteins of translation. The partial DMOG-mediated arrest of the synthesis of mitochondrial and translation proteins results from the inhibition of the mTORC1/p7OSK/S6 signaling pathway. In contrast, DMOG stimulated the synthesis of glycolytic enzymes, emphasizing the opposite and differential regulation of the two pathways of energy provision. Addition of MitoQ a mitochondrial reactive oxygen species (mtROS) scavenger, stabilized the turnover of cellular proteins similarly as when protein degradation is inhibited with leupeptin, a serine-protease inhibitor. Overall, the results show that the higher the activity of a pathway the lower is the half-life of the proteins involved and suggest a role for mtROS in cellular proteostasis. Data are available via ProteomeXchange with identifier PXD013482.
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