Metabolic transitions regulate global protein fatty acylation

Area of Science:

• Biochemistry
• Cellular Metabolism
• Molecular Biology

Background:

• Intermediary metabolites and pathway flux influence post-translational modifications.
• Intracellular fatty acid pools fluctuate between fed and fasted states, impacting ATP production and protein fatty acylation.
• The effect of intracellular fatty acid concentrations on protein modification remains less understood.

Purpose of the Study:

• To demonstrate how metabolic contexts dictate global protein fatty acylation.
• To investigate the influence of glucose availability on fatty acid metabolism and protein modification.
• To elucidate the role of mitochondria and retrograde signaling in orchestrating protein fatty acylation.

Main Methods:

• Utilized click-chemistry, lipidomics, and imaging techniques.
• Employed complementary approaches to study cellular metabolic states.
• Performed pharmacogenetic perturbations to alter mitochondrial functions and retrograde signaling.

Main Results:

• Metabolic contexts (fed/fasted states) significantly dictate global protein fatty acylation.
• Glucose availability influences fatty acid uptake/utilization and impacts palmitoylation and oleoylation.
• Mitochondria and retrograde signaling components (SIRT4, AMPK, mTOR) are critical for regulating protein fatty acylation.

Conclusions:

• Cellular metabolic state exerts top-down control over protein fatty acylation.
• Mitochondrial energetics and retrograde signaling are key players in mediating this post-translational modification.
• Findings highlight the cross-talk between carbohydrate and lipid metabolism in regulating protein modification.