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J. Biol. Chem., Vol. 281, Issue 49, 37361-37371, December 8, 2006

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Mitochondrial Creatine Kinase Activity Prevents Reactive Oxygen Species Generation

ANTIOXIDANT ROLE OF MITOCHONDRIAL KINASE-DEPENDENT ADP RE-CYCLING ACTIVITY^*

Laudiene Evangelista Meyer¹, Lilia Bender Machado¹, Ana Paula S. A. Santiago, Wagner Seixas da-Silva², Fernanda G. De Felice, Oliver Holub, Marcus F. Oliveira¹³, and Antonio Galina¹⁴

From the Instituto de Bioquímica Médica, Programa de Biofísica e Bioquímica Celular and Programa de Biologia Molecular e Biotecnologia and the Instituto de Biofísica Carlos Chagas Filho, Programa de Biologia Celular e Parasitologia, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Rio de Janeiro 21941-590, Brazil

As recently demonstrated by our group (da-Silva, W. S., Gómez-Puyou, A., Gómez-Puyou, M. T., Moreno-Sanchez, R., De Felice, F. G., de Meis, L., Oliveira, M. F., and Galina, A. (2004) J. Biol. Chem. 279, 39846–39855) mitochondrial hexokinase activity (mt-HK) plays a preventive antioxidant role because of steady-state ADP re-cycling through the inner mitochondrial membrane in rat brain. In the present work we show that ADP re-cycling accomplished by the mitochondrial creatine kinase (mt-CK) regulates reactive oxygen species (ROS) generation, particularly in high glucose concentrations. Activation of mt-CK by creatine (Cr) and ATP or ADP, induced a state 3-like respiration in isolated brain mitochondria and prevention of H₂O₂ production obeyed the steady-state kinetics of the enzyme to phosphorylate Cr. The extension of the preventive antioxidant role of mt-CK depended on the phosphocreatine (PCr)/Cr ratio. Rat liver mitochondria, which lack mt-CK activity, only reduced state 4-induced H₂O₂ generation when 1 order of magnitude more exogenous CK activity was added to the medium. Simulation of hyperglycemic conditions, by the inclusion of glucose 6-phosphate in mitochondria performing 2-deoxyglucose phosphorylation via mt-HK, induced H₂O₂ production in a Cr-sensitive manner. Simulation of hyperglycemia in embryonic rat brain cortical neurons increased both _m and ROS production and both parameters were decreased by the previous inclusion of Cr. Taken together, the results presented here indicate that mitochondrial kinase activity performed a key role as a preventive antioxidant against oxidative stress, reducing mitochondrial ROS generation through an ADP-recycling mechanism.

Received for publication, May 1, 2006 , and in revised form, September 5, 2006.

^* This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Fundação Universitária José Bonifácio, and the Third World Academy of Sciences. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S2.

¹ These authors contributed equally to the results of this work.

² Present address: Thyroid Section, Division of Endocrinology, Diabetes, and Hypertension, Dept. of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.

³ Research fellow of CNPq. To whom correspondence may be addressed: Av. Brigadeiro Trompowsky, s/n, CCS, Bloco D, sub-solo sala D-013 and D-005, Laboratory of Bioenergetic and Mitochondrial Physiology Cidade Universitária, Rio de Janeiro, RJ 21941-590, Brazil. E-mail: maroli{at}bioqmed.ufrj.br. ⁴ Research fellow of CNPq. To whom correspondence may be addressed: E-mail: galina{at}bioqmed.ufrj.br.

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