Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos).

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 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 Pduanyu37-1 and nuclear translocation of AIF. Further study showed that Pduanyu37-1 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.

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