c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate.

Abstract

myc(-/-) rat fibroblasts (KO cells) differ from myc(+/+) (WT) cells and KO cells with enforced Myc re-expression (KO-Myc cells) with respect to mitochondrial structure and function, utilization of glucose and glutamine as energy-generating substrates, and ATP levels. Specifically, KO cells demonstrate low levels of glycolysis and oxidative phosphorylation, dysfunctional mitochondria and electron transport chain complexes, and depleted ATP stores. We examined here how these cells adapt to their energy-deficient state and how they differ in their uptake and utilization of long- and medium-chain fatty acids such as palmitate and octanoate, respectively. Metabolic tracing of these molecules showed that KO cells preferentially utilize them as β-oxidation substrates and that, rather than directing them into phospholipids, preferentially store them as neutral lipids. KO cell transcriptional profiling and functional assays revealed a generalized up-regulation of pathways involved in fatty acid transport and catabolism as well as evidence that these cells attempt to direct acetyl-CoA into the tricarboxylic acid (TCA) cycle for ATP production rather than utilizing it for anabolic purposes. Additional evidence to support this idea included the finding that AMP-dependent protein kinase was constitutively activated in KO cells. The complex control of pyruvate dehydrogenase, which links glycolysis to the TCA cycle, was also maximized to ensure the conversion of pyruvate to acetyl-CoA. Despite these efforts to maximize acetyl-CoA for energy-generating purposes, its levels remained chronically low in KO cells. This suggests that tumor cells with Myc deregulation might be susceptible to novel therapies that limit acetyl-CoA availability.

• Authors: Lia R Edmunds, Lokendra Sharma, Audry Kang, Jie Lu, Jerry Vockley, Shrabani Basu, Radha Uppala, Eric S Goetzman, Megan E Beck, Donald Scott, Edward V Prochownik
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 36 Pg. 25382-92 (Sep 05 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25053415 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Fatty Acids
• Proto-Oncogene Proteins c-myc
• Acetyl Coenzyme A
• Pyruvic Acid
• Adenosine Triphosphate
• Ketone Oxidoreductases
• pyruvate dehydrogenase (NADP+)
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Acetyl Coenzyme A (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Blotting, Western
• Cell Line, Tumor
• Citric Acid Cycle
• Fatty Acids (metabolism)
• Fibroblasts (cytology, metabolism)
• Gene Expression Profiling
• Gene Knockout Techniques
• Glycolysis
• Humans
• Ketone Oxidoreductases (genetics, metabolism)
• Lipid Metabolism
• Metabolic Networks and Pathways (genetics)
• Oxidation-Reduction
• Oxidative Phosphorylation
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyruvic Acid (metabolism)
• RNA Interference
• Rats
• Reverse Transcriptase Polymerase Chain Reaction