Activation of a PGC-1-related coactivator (PRC)-dependent inflammatory stress program linked to apoptosis and premature senescence.
PGC-1-related coactivator (PRC), a growth-regulated member of the PGC-1 coactivator family, contributes to the expression of the mitochondrial respiratory apparatus. PRC also orchestrates a robust response to metabolic stress by promoting the expression of multiple genes specifying inflammation, proliferation, and metabolic reprogramming. Here, we demonstrate that this PRC-dependent stress program is activated during apoptosis and senescence, two major protective mechanisms against cellular dysfunction. Both PRC and its targets (IL1α, SPRR2D, and SPRR2F) were rapidly induced by menadione, an agent that promotes apoptosis through the generation of intracellular oxidants. Menadione-induced apoptosis and the PRC stress program were blocked by the antioxidant N-acetylcysteine. The PRC stress response was also activated by the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38), an inducer of premature senescence in tumor cells. Cells treated with SN-38 displayed morphological characteristics of senescence and express senescence-associated β-galactosidase activity. In contrast to menadione, the SN-38 induction of the PRC program occurred over an extended time course and was antioxidant-insensitive. The potential adaptive function of the PRC stress response was investigated by treating cells with meclizine, a drug that promotes glycolytic energy metabolism and has been linked to cardio- and neuroprotection against ischemia-reperfusion injury. Meclizine increased lactate production and was a potent inducer of the PRC stress program, suggesting that PRC may contribute to the protective effects of meclizine. Finally, c-MYC and PRC were coordinately induced under all conditions tested, implicating c-MYC in the biological response to metabolic stress. The results suggest a general role for PRC in the adaptive response to cellular dysfunction.
Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611.
Natalie
N
Gleyzer
Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611. Electronic address: rsc248@northwestern.edu.
Richard C
RC
Scarpulla
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D000077146:Irinotecan; D007700:Kinetics; D008468:Meclizine / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D061209:Proton Ionophores / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D024483:Vitamin K 3 / Q000494:pharmacology
D000975:Antioxidants; D055233:Cornified Envelope Proline-Rich Proteins; D006634:Histamine H1 Antagonists; C489427:MYC protein, human; D016877:Oxidants; D016271:Proto-Oncogene Proteins c-myc; D061209:Proton Ionophores; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D008468:Meclizine; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D024483:Vitamin K 3; D000077146:Irinotecan; D000111:Acetylcysteine; D002166:Camptothecin