title: Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos).
abstract: Oxidative stress-induced cell death is common in many neurological diseases. However, the role of poly(ADP-ribose) polymerase-1-induced cell death (parthanatos) has not been fully elucidated. Here, we found that hydrogen peroxide (H2O2) could lead to PARP-1 activation and apoptosis-inducing factor nuclear translocation in a concentration dependent manner. Iduna, as a novel regulator of parthanatos, was also induced by H2O2. Down-regulation of Iduna by genetic ablation promoted H2O2-induced cell damage. Up-regulation of Iduna reduced the loss of mitochondrial potential and ATP and NAD+ production, but did not affect the mitochondrial dysfunction-induced cytochrome c release, increase of Bax/Bcl-2 ratio, and Caspase-9/Caspase-3 activity. In contrast, overexpression of Iduna inhibited activation of PARP-1 and nuclear translocation of AIF. Further study showed that PARP-1 specific inhibitor, DPQ, blocked the protective effect of Iduna against H2O2-induced oxidative stress. Moreover, in the presence of proteasome inhibitor (MG-132) or ubiquitin E1 inhibitor (PYR-41), protective effect of Iduna was significantly weaken. These results indicate that Iduna acts as a potential antioxidant by improving mitochondrial function and inhibiting oxidative stress-induced parthanatos, and these protective effects are dependent on the involvement of ubiquitin-proteasome system.
authors: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors: Haoxiang
authors: H
authors: Xu
authors: Peng
authors: P
authors: Luo
authors: Yongbo
authors: Y
authors: Zhao
authors: Mingming
authors: M
authors: Zhao
authors: Yuefan
authors: Y
authors: Yang
authors: Tao
authors: T
authors: Chen
authors: Kai
authors: K
authors: Huo
authors: Hua
authors: H
authors: Han
authors: Zhou
authors: Z
authors: Fei
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007976:Leupeptins / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C523934:4(4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl)-benzoic acid ethyl ester; D001565:Benzoates; D005663:Furans; D007976:Leupeptins; D011720:Pyrazoles; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D009243:NAD; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C583436:Rnf146 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053181:Caspase 8; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde