Essential Role for Mitochondrial Thioredoxin Reductase in Hematopoiesis, Heart Development, and Heart Function

Abstract

Oxygen radicals regulate many physiological processes, such as signaling, proliferation, and apoptosis, and thus play a pivotal role in pathophysiology and disease development. There are at least two thioredoxin reductase/ thioredoxin/peroxiredoxin systems participating in the cellular defense against oxygen radicals. At present, relatively little is known about the contribution of individual enzymes to the redox metabolism in different cell types. To begin to address this question, we generated and characterized mice lacking functional mitochondrial thioredoxin reductase (TrxR2). Ubiquitous Cre-mediated inactivation of TrxR2 is associated with embryonic death at embryonic day 13. TrxR2 ؊/؊ embryos are smaller and severely anemic and show increased apoptosis in the liver. The size of hematopoietic colonies cultured ex vivo is dramatically reduced. TrxR2-deficient embryonic fibroblasts are highly sensitive to endogenous oxygen radicals when glutathione synthesis is inhibited. Besides the defect in hematopoiesis, the ventricular heart wall of TrxR2 ؊/؊ embryos is thinned and proliferation of cardiomyocytes is decreased. Cardiac tissue-restricted ablation of TrxR2 results in fatal dilated cardiomyopathy, a condition reminiscent of that in Keshan disease and Friedreich's ataxia. We conclude that TrxR2 plays a pivotal role in both hematopoiesis and heart function.Reactive oxygen species (ROS)-generated mainly as a byproduct of the respiratory chain or by oxidases-are implicated in the pathogenesis and pathophysiology of a variety of human diseases such as cancer, cardiovascular, and degenerative disorders. A variety of cellular antioxidant systems control the balance of free intra-and extracellular oxygen radicals. Previous efforts have addressed the physiological role of superoxide dismutases, catalases, and glutathione (GSH) peroxidases in vivo, but the role of the thioredoxin/thioredoxin reductase/ peroxiredoxin system in ROS removal has only recently attracted attention.Thioredoxins are small redox-active proteins with an essential function in DNA metabolism and repair, transcription, and cell-cell communication (1). Acting through peroxiredoxins, they also efficiently protect cells from oxidative damage (27). Cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins are required for proliferation and protection from apoptosis during early embryogenesis (26). Moreover, in chicken B cells, Trx2 is critically involved in the regulation of mitochondriondependent apoptosis (37). More recently, heart-specific overexpression of dominant-negative Trx1 was shown to be associated with increased oxidative stress and cardiac hypertrophy in mice (39).Trx activities are governed by thioredoxin reductases (TrxRs) that, in turn, use NADPH/H ϩ as the reducing agent (23). TrxRs are members of the pyridine nucleotide-disulfide oxidoreductase family, form homodimers, and possess two interacting redox-active centers. The C-terminal redox center contains a catalytically important selenocysteine (SeCys) (9,17,41). In mammals, three TrxRs...

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…The impact of altered redox homeostasis in loss of neuromuscular integrity and function with ageing has been investigated in several murine models, which have undergone genetic modifications of redox signalling/homeostasis components 19, 23, 25, 29, 30, 31, 32, 33, 34, 240, 241, 242. Transgenic murine models have provided insight into the importance of RONS regulatory systems in lifespan and neuromuscular ageing, and it has been reported that SOD2 −/− ,243 GRX3 −/− ,244 GPX4 −/− ,245 TRX1 −/− ,246 TRX2 −/− ,247 TR1 −/− 248 and TR2 −/− 249 murine models are embryonically lethal. Although the embryonic lethal phenotypes observed in these specific knockout models do not facilitate our understanding on whether defects in redox signalling affect age‐dependent deficits in neuromuscular integrity and function, these findings, however, highlight the fundamental importance of the redox systems mentioned in the preceding text during embryonic development.…”

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

“…Previous studies have demonstrated that many tumor processes are closely related to TrxR, including growth, metastasis and inhibition of apoptosis [1][2][3][4][5]17] . Ethaselen is a small molecule that is specifically combined with TrxR and reduces the TrxR activity levels, exerting good inhibitory effects on several human carcinoma cell lines [11][12][13][14][15]26] .…”

“…It has been reported that TrxR is involved in many aspects of tumor physiology, such as proliferation, apoptosis and metastasis [1][2][3][4][5] . In recent years, an increasing number of TrxR inhibitors have received attention and have eventually been demonstrated as effective [7,[27][28][29] ; Ethaselen is one promising, potent candidate [26] .…”

“…Mammalian thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate some physiological processes, especially cell survival, maturation, growth, migration and inhibition of apoptosis [1][2][3][4][5][6] . The TrxR1 expression levels in some human carcinoma cell lines are approximately 10 times higher than those in normal cells [7] , indicating their close relationships with cell proliferation and progression.…”

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“…As observed for the TrxR1, complete removal of mitochondrial TrxR2 causes embryonic death at around day 13 (76,245). TrxR2 homozygous mutant embryos showed decreased hematopoiesis, increased apoptosis in the liver, and cardiac defects (76).…”