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J. Biol. Chem., Vol. 280, Issue 42, 35767-35775, October 21, 2005

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Pivotal Role of Akt Activation in Mitochondrial Protection and Cell Survival by Poly(ADP-ribose)polymerase-1 Inhibition in Oxidative Stress^*

Antal Tapodi, Balazs Debreceni, Katalin Hanto, Zita Bognar, Istvan Wittmann¶, Ferenc Gallyas, Jr., Gabor Varbiro, and Balazs Sumegi||1

From the Department of Biochemistry and Medical Chemistry, First Department of Medicine, Division of Cardiology, ^¶Second Department of Medicine, Faculty of Medicine, and the ^||Hungarian Academy of Sciences, Research Group for Mitochondrial Function and Mitochondrial Diseases, Faculty of Medicine, University of Pecs, 12 Szigeti Street, Pecs 7624, Hungary

According to the classical view, the cytoprotective effect of inhibitors of poly(ADP-ribose)polymerase (PARP) in oxidative stress was based on the prevention of NAD⁺ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.

Received for publication, June 29, 2005 , and in revised form, August 16, 2005.

^* This work was supported by Hungarian Science Foundation Grant T046473, Ministry of Health and Welfare Grants ETT 559/2003, PTE-DD-KKK, and OMFB 01603/02, and Hungarian Academy of Science Grant MTA TKI 14009. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 36-72-536-276; Fax: 36-72-536-277; E-mail: balazs.sumegi{at}aok.pte.hu.

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