Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis

Tanaka, Toru; Hosoi, Fumihito; Yamaguchi-Iwai, Yuko; Nakamura, Hajime; Masutani, Hiroshi; Ueda, Shugo; Nishiyama, Akira; Takeda, Shunichi; Wada, Hiromi; Spyrou, Giannis; Yodoi, Junji

doi:10.1093/emboj/21.7.1695

Cited by 291 publications

(207 citation statements)

References 33 publications

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“…We have recently reported that Trx-2 played a crucial role in the scavenging ROS in mitochondria and regulating the mitochondrial apoptosis signaling pathways using the conditional Trx-2-deficient cells expressing a tetracycline (tet)-repressible TRX-2 transgene in DT 40 cell line. 44 More interestingly, Trx-2 inhibits the release of cytochrome c through the direct binding to cytochrome c in mitochondria. Hence, the role of Trx-2 in Tg mice is to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice

et al. 2003

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“…Protection against oxidant-induced apoptosis was observed in 143B osteosarcoma cells and SH-SY5Y human neuroblastoma cells with the nonradical reductant mitochondrial Trx-2 (28,29). Decreased mitochondrial Trx-2 in DT40 chicken B cells increased oxidants and caused spontaneous apoptosis (175). Similarly, decrease in the Trx-2-dependent peroxidase Prx3 increased H 2 O 2 and sensitized HeLa cells to staurosporine-or TNF-␣-induced apoptosis (26).…”

Section: Oxidative Stress As a Disruption Of Redox Signaling And Controlmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

979

815

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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“…Recent studies suggest that the mitochondrial Trx system is essential for mammalian development because disruption of the Trx2 gene in the mouse confers a lethal embryonic phenotype associated with massive apoptosis during early embryogenesis (23). Chicken cells (DT40) conditionally deficient for Trx2 expression have been reported to undergo apoptosis in the absence of exogenous stress (24). In addition, glutathione depletion, serum withdrawal, and exposure to the prooxidant mitochondrial toxin, antimycin A, were all shown to enhance apoptosis in Trx2-deficient DT40 cells (24,25).…”

mentioning

confidence: 99%

“…Chicken cells (DT40) conditionally deficient for Trx2 expression have been reported to undergo apoptosis in the absence of exogenous stress (24). In addition, glutathione depletion, serum withdrawal, and exposure to the prooxidant mitochondrial toxin, antimycin A, were all shown to enhance apoptosis in Trx2-deficient DT40 cells (24,25). On the other hand, overexpression of Trx2 was reported to enhance basal ⌬ m and protect human HEK-293 Trx2-transfected cells against etoposide-mediated cytotoxicity.…”

mentioning

confidence: 99%

Mitochondrial Thioredoxin System

Patenaude

Murthy

Mirault

2004

Journal of Biological Chemistry

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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. EGFPTrxR2 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.A drastic alteration of the mitochondrial redox environment, which includes rapid oxidation of NAD(P)H and glutathione, is one of the earliest events of the mitochondrial pathway of apoptosis (1-3). This phenomenon is associated with dissipation of the mitochondrial transmembrane potential (⌬ m ) and subsequent induction of reactive oxygen species (ROS) 1 generation (4). Onset of mitochondrial membrane permeabilization (MMP), a decisive step in the mitochondrial pathway of apoptosis, is regulated by both pyridine nucleotide (NAD/NADH and NADP ϩ /NADPH) and glutathione (GSSG/GSH) redox equilibrium (5, 6). Protein thiol (sulfhydryl) groups can be oxidized directly or indirectly by ROS, i.e. via GSH oxidation and mixed disulfide formation, such as glutathiolation. For example, specific thiol groups on the adenine nucleotide translocator (ANT), an inner membrane constituent of the mitochondrial permeability transition pore complex, have been implicated in modulating MMP. Oxidation of Cys-56 and crosslinking of Cys-56 to Cys-159 were shown to convert the ADP/ ATP translocase into an opened nonspecific pore, a pr...

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Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis

Cited by 291 publications

References 33 publications

Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice

Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopolysaccharide in mice

Radical-free biology of oxidative stress

Mitochondrial Thioredoxin System

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