c-Myc and AMPK Control Cellular Energy Levels by Cooperatively Regulating Mitochondrial Structure and Function

Area of Science:

• Cellular Metabolism
• Oncogenesis
• Mitochondrial Function

Background:

• The c-Myc (Myc) oncoprotein and AMP-activated protein kinase (AMPK) are key regulators of cellular energy metabolism, controlling glycolysis and oxidative phosphorylation (Oxphos).
• Myc overexpression can lead to ATP depletion, activating AMPK, suggesting a potential interplay between these pathways.

Purpose of the Study:

• To investigate the co-dependency and cross-talk between Myc and AMPK in regulating cellular metabolism.
• To compare the metabolic consequences of acute Myc induction in wild-type (WT) and AMPK-deficient (KO) murine embryo fibroblasts (MEFs).

Main Methods:

• Comparison of metabolic profiles (glycolysis, Oxphos, mitochondrial mass, ROS production) in WT and KO MEFs following Myc-estrogen receptor (MycER) activation.
• Analysis of electron transport chain function, TCA cycle intermediates, redox states, and transcriptional changes.
• Unbiased mass spectrometry-based proteomic survey of mitochondrial proteins and enzyme activity assays.

Main Results:

• AMPK-deficient MEFs exhibited higher basal glycolysis but a reduced capacity for increased Oxphos, mitochondrial mass, and ROS production upon MycER activation.
• Significant differences in electron transport chain function, TCA cycle enzyme levels, and redox states were observed between WT and KO MEFs.
• Mass spectrometry revealed ~15% of quantified mitochondrial proteins to be dependent on either AMPK or Myc, or both, impacting key metabolic enzymes like pyruvate kinase and pyruvate dehydrogenase.

Conclusions:

• Myc and AMPK exhibit significant co-dependency and cross-talk in regulating metabolic pathways essential for ATP generation.
• This interplay influences glycolysis, oxidative phosphorylation, and mitochondrial function, highlighting a complex regulatory network in cellular energy homeostasis.