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J. Biol. Chem., Vol. 279, Issue 26, 27302-27314, June 25, 2004

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Mitochondrial Thioredoxin System

EFFECTS OF TrxR2 OVEREXPRESSION ON REDOX BALANCE, CELL GROWTH, AND APOPTOSIS^*

Alexandre Patenaude, M. R. Ven Murthy¶, and Marc-Edouard Mirault||

From the Departments of Medicine and ^¶Medical Biology, Faculty of Medicine, Laval University, and CHUL/CHUQ Medical Research Center, Québec City, Québec G1V 4G2, Canada

Thioredoxin-2 (Trx2) is a mitochondrial protein-disulfide oxidoreductase essential for control of cell survival during mammalian embryonic development. This suggests that mitochondrial thioredoxin reductase-2 (TrxR2), responsible for reducing oxidized Trx2, may also be a key player in the regulation of mitochondria-dependent apoptosis. With this in mind, we investigated the effects of overexpression of TrxR2, Trx2, or both on mammalian cell responses to various apoptotic inducers. Stable transfectants of mouse Neuro2A cells were generated that overexpressed TrxR2 or an EGFP-TrxR2 fusion protein. EGFP-TrxR2 was enzymatically active and was localized in mitochondria. TrxR2 protein level and TrxR activity could be increased up to 6-fold in mitochondria. TrxR2 and EGFP-TrxR2 transfectants showed reduced growth rates as compared with control cells. This growth alteration was not due to cytotoxic effects nor related to changes in basal mitochondrial transmembrane potential (_m), reactive oxygen species production, or to other mitochondrial antioxidant components such as Trx2, peroxyredoxin-3, MnSOD, GPx1, and glutathione whose levels were not affected by increased TrxR2 activity. In response to various apoptotic inducers, the extent of _m dissipation, reactive oxygen species induction, caspase activation, and loss of viability were remarkably similar in TrxR2 and control transfectants. Excess TrxR2 did not prevent trichostatin A-mediated neuronal differentiation of Neuro2A cells nor did it protect them against -amyloid neurotoxicity. Neither massive glutathione depletion nor co-transfection of Trx2 and TrxR2 in Neuro2A (mouse), COS-7 (monkey), or HeLa (human) cells revealed any differential cellular resistance to prooxidant or non-oxidant apoptotic stimuli. Our results suggest that neither Trx2 nor TrxR2 gain of function modified the redox regulation of mitochondria-dependent apoptosis in these mammalian cells.

Received for publication, March 4, 2004

^* This work was supported by National Institutes of Health Grant RO1NS37718 and Subcontract NMRI98001 with the Natural Medicines Research Institute (to M. R. V. M. and M.-E. M.), and by the National Cancer Institute of Canada through Canadian Cancer Society Grants 2796 and 3488 (to M.-E. M.). 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.

^|| To whom correspondence should be addressed: Dept. of Medicine, Entre Hospitalier de Laval University, 2705 Blvd. Laurier, Québec G1V 4G2, Canada. Tel.: 418-656-4141 (ext. 47097); Fax: 418-654-2159; E-mail: memirault{at}crchul.ulaval.ca.

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