A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress

• Published in: Cell death and differentiation Vol. 16; no. 2; pp. 264 - 277
• Main Authors: Huang, Q, Wu, Y-T, Tan, H-L, Ong, C-N, Shen, H-M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2009; Nature Publishing Group
• Subjects: Alzheimer's disease; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; DNA damage; Fibroblasts - drug effects; Gene Knockdown Techniques; Hydrogen Peroxide - pharmacology; Kinases; Life Sciences; Medicine; Metabolism; Mice; Models, Biological; Necrosis; original-paper; Oxidative Stress; Physiology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteins; Stem Cells; TOR Serine-Threonine Kinases; Singapore; mTOR; AMPK; autophagy; necrosis; PARP-1; ROS
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2008.151

Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H
2
O
2
) induces necrotic cell death in
Bax−/− Bak−/−
mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H
2
O
2
. More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H
2
O
2
-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H
2
O
2
-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK–mTOR pathway to enhance cell survival in cells under oxidative stress.