1. Academic Validation
  2. Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction

Concerted Action of PGC-1-related Coactivator (PRC) and c-MYC in the Stress Response to Mitochondrial Dysfunction

  • J Biol Chem. 2016 Dec 2;291(49):25529-25541. doi: 10.1074/jbc.M116.719682.
Natalie Gleyzer 1 Richard C Scarpulla 2
Affiliations

Affiliations

  • 1 From the Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611.
  • 2 From the Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611 rsc248@northwestern.edu.
Abstract

PGC-1-related coactivator (PRC) has a dual function in growth-regulated mitochondrial biogenesis and as a sensor of metabolic stress. PRC induction by mitochondrial inhibitors, intracellular ROS, or Topoisomerase I inhibition orchestrates an inflammatory program associated with the adaptation to cellular stress. Activation of this program is accompanied by the coordinate expression of c-Myc, which is linked kinetically to that of PRC in response to multiple stress inducers. Here, we show that the c-Myc Inhibitor 10058-F4 blocks the induction of c-Myc, PRC, and representative PRC-dependent stress genes by the respiratory chain uncoupler, carbonyl cyanide m-chlorophenyl hydrazine (CCCP). This result, confirmed by the suppression of PRC induction by c-Myc siRNA silencing, demonstrates a requirement for c-Myc in orchestrating the stress program. PRC steady-state expression was markedly increased upon mutation of two GSK-3 serine phosphorylation sites within the carboxyl-terminal domain. The negative control of PRC expression by GSK-3 was consistent with the phosphor-inactivation of GSK-3β by CCCP and by the induction of PRC by the GSK-3 Inhibitor AZD2858. Unlike PRC, which was induced post-translationally through increased protein half-life, c-Myc was induced predominantly at the mRNA level. Moreover, suppression of Akt activation by the Akt Inhibitor MK-2206 blocked the CCCP induction of PRC, c-Myc, and representative PRC stress genes, demonstrating a requirement for Akt signaling. MK-2206 also inhibited the phosphor-inactivation of GSK-3β by CCCP, a result consistent with the ability of Akt to phosphorylate, and thereby suppress GSK-3 activity. Thus, PRC and c-Myc can act in concert through Akt-GSK-3 signaling to reprogram gene expression in response to mitochondrial stress.

Keywords

gene regulation; metabolism; mitochondria; signaling; stress.

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