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

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.

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

“…PRC, which is expressed ubiquitously, also enhances the gene transcription of NRF1. PRC mainly regulates gene expression in proliferating cells and in growth‐regulated mitochondrial biogenesis . PRC depletion results in the aggregation of atypical mitochondria and severe respiratory chain dysfunction …”

NO control of mitochondrial function in normal and transformed cells

“…PRC1 is a relevant regulator of mitochondrial function in cells where PGC-1α is absent and mediates the activation of respiratory genes through transcription factors (101). However, the physiological role of PRC1 is still debated (102). Similar to PGC-1α, PRC1 also binds to nuclear transcription factors implicated in the expression of mitochondrial function, including NRF-1, cAMP response element-binding protein 1 (CREB) and estrogen-related receptor alpha (ERRalpha) (103).…”

“…Thus depending on the cell type, we can have different isoforms acting in similar pathways. More recently, it was found that PRC1 and c-MYC can act in concert to reprogram gene expression in response to mitochondrial stress, providing an additional link between PRC1 and cancer (102)(Fig.3). …”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…Peroxisome proliferators activated receptor gamma co-activator 1 alpha (PGC-1α), known to be the regulatory master in orchestrating mitochondrial biogenesis, has been shown to be mediated by GSK-3β in mitochondria [4]. Phosphor-inactivation of GSK-3β induces the expression of PGC-1-related coactivator (PRC), which is involved in both mitochondrial biogenesis and sensitivity of metabolic stress [5]. Recently, GSK-3β signaling has been demonstrated to be implicated in regulation of mitochondrial permeability transition pore (mPTP) opening, controlling cell fates [6].…”