Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy

Sibbing, Dirk; Pfeufer, Arne; Perisic, Tamara; Mannes, Alexander M.; Fritz‐Wolf, Karin; Unwin, Sarah; Sinner, Moritz F.; Gieger, Christian; Gloeckner, Christian Johannes; Wichmann, Heinz‐Erich; Kremmer, Elisabeth; Schäfer, Zasie; Walch, Axel; Hinterseer, Martin; Näbauer, Michael; Kääb, Stefan; Kastrati, Adnan; Schömig, Albert; Meitinger, Thomas; Bornkamm, Georg W.; Conrad, Marcus; Beckerath, Nicolas von

doi:10.1093/eurheartj/ehq507

Cited by 85 publications

(47 citation statements)

References 33 publications

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“…40 In the present study, we provide evidence for an essential role of endogenous mitochondrial Txnrd2 in controlling I/R injury of the heart. To this end, we used mice in which exons 15-18 of the remaining Txnrd2 allele were flanked by Lox-P sites.…”

Section: Discussionsupporting

confidence: 51%

Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection

et al. 2011

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Background— Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury. Methods and Results— In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen ( Txnrd2-/-ic ), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours). Txnrd2-/-ic was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered. Conclusions— We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.

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Section: Discussionsupporting

confidence: 51%

Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection

et al. 2011

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“…20 Nothing, however, is known on the role of the upstream enzyme, mitochondrial Txnrd2 in the vasculature or specifically in ECs, despite its vital importance, as demonstrated in other organs. 21 Thus, 2 mutations in the flavinadenine dinucleotide-binding domain of human TXNRD2 have been observed in some patients with dilated cardiomyopathy, 22 and we and associated laboratories have confirmed this enzyme's importance in the heart in a cardiomyocytespecific knockout mouse. 21,23,24 Having successfully generated a Tamoxifen-inducible, EC-specific Txnrd2 knockout mouse (Txnrd2 iECKO ), we hypothesized that elevated ROS originating from the mitochondria of ECs will affect general vascular function and impair vascular remodeling processes in a model of femoral artery ligation.…”

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confidence: 73%

Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium

Kirsch

Schneider

Pagel

et al. 2016

ATVB

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Objective— Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell–specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control. Approach and Results— We analyzed the impact of an inducible, endothelial cell–specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation. Laser Doppler analysis and histology revealed impaired angiogenesis and arteriogenesis. In addition, endothelial loss of Txnrd2 resulted in a prothrombotic, proinflammatory vascular phenotype, manifested as intravascular cellular deposits, as well as microthrombi. This phenotype was confirmed by an increased leukocyte response toward interleukin-1 in the mouse cremaster model. In vitro, we could confirm the attenuated angiogenesis measured in vivo, which was accompanied by increased ROS and an impaired mitochondrial membrane potential. Ex vivo analysis of femoral arteries revealed reduced flow-dependent vasodilation in endothelial cell Txnrd2-deficient mice. This endothelial dysfunction could be, at least partly, ascribed to inadequate nitric oxide signaling. Conclusions— We conclude that the maintenance of mitochondrial ROS via Txnrd2 in endothelial cells is necessary for an intact vascular homeostasis and remodeling and that Txnrd2 plays a vitally important role in balancing mitochondrial ROS production in the endothelium.

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“…Nevertheless, TXNRD2 is in the same pathway of ROS detoxification and TXNRD2 heterozygous mutations in humans have also been linked to dilated cardiomyopathy. Thus, for now, cardiac follow-up should be done (10,36).…”

Section: Discussionmentioning

confidence: 99%

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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Objective: Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. Methods: Sanger or massive parallel sequencing of NNT and patient monitoring. Results: Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. Conclusions: NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

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Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy

Abstract: For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.

Cited by 85 publications

References 33 publications

Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection

Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection

Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

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