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C-Myc and AMPK control cellular energy levels by cooperatively regulating mitochondrial structure and function

Edmunds, LR and Sharma, L and Wang, H and Kang, A and D'Souza, S and Lu, J and McLaughlin, M and Dolezal, JM and Gao, X and Weintraub, ST and Ding, Y and Zeng, X and Yates, N and Prochownik, EV (2015) C-Myc and AMPK control cellular energy levels by cooperatively regulating mitochondrial structure and function. PLoS ONE, 10 (7).

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Abstract

The c-Myc (Myc) oncoprotein and AMP-activated protein kinase (AMPK) regulate glycolysis and oxidative phosphorylation (Oxphos) although often for different purposes. Because Myc over-expression depletes ATP with the resultant activation of AMPK, we explored the potential co-dependency of and cross-talk between these proteins by comparing the consequences of acute Myc induction in ampk+/+ (WT) and ampk-/-(KO) murine embryo fibroblasts (MEFs). KO MEFs showed a higher basal rate of glycolysis than WT MEFs and an appropriate increase in response to activation of a Myc-estrogen receptor (MycER) fusion protein. However, KO MEFs had a diminished ability to increase Oxphos, mitochondrial mass and reactive oxygen species in response to MycER activation. Other differences between WT and KO MEFs, either in the basal state or following MycER induction, included abnormalities in electron transport chain function, levels of TCA cycle-related oxidoreductases and cytoplasmic and mitochondrial redox states. Transcriptional profiling of pathways pertinent to glycolysis, Oxphos and mitochondrial structure and function also uncovered significant differences between WT and KO MEFs and their response to MycER activation. Finally, an unbiased mass-spectrometry (MS)-based survey capable of quantifying ∼40% of all mitochondrial proteins, showed about 15% of them to be AMPK-and/or Myc-dependent in their steady state. Significant differences in the activities of the rate-limiting enzymes pyruvate kinase and pyruvate dehydrogenase, which dictate pyruvate and acetyl coenzyme A abundance, were also differentially responsive to Myc and AMPK and could account for some of the differences in basal metabolite levels that were also detected by MS. Thus, Myc and AMPK are highly co-dependent and appear to engage in significant cross-talk across numerous pathways which support metabolic and ATP-generating functions. Copyright:

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Edmunds, LRLia.Edmunds@pitt.eduLRE13
Sharma, L
Wang, Hhuw14@pitt.eduHUW14
Kang, A
D'Souza, S
Lu, Jjil75@pitt.eduJIL75
McLaughlin, Mmlm201@pitt.eduMLM201
Dolezal, JMjmd172@pitt.eduJMD172
Gao, X
Weintraub, ST
Ding, YYINGDING@pitt.eduYINGDING
Zeng, X
Yates, NYATESN@pitt.eduYATESN
Prochownik, EVevp4@pitt.eduEVP4
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSobol, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Date: 31 July 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0134049
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Biostatistics
School of Medicine > Cell Biology
School of Medicine > Medicine
School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Date Deposited: 23 Aug 2016 14:26
Last Modified: 30 Mar 2021 19:55
URI: http://d-scholarship.pitt.edu/id/eprint/28410

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