Thioredoxin-1 maintains mitochondrial function via mechanistic target of rapamycin signalling in the heart

Abstract

Aims Thioredoxin 1 (Trx1) is an evolutionarily conserved oxidoreductase that cleaves disulphide bonds in oxidized substrate proteins such as mechanistic target of rapamycin (mTOR) and maintains nuclear-encoded mitochondrial gene expression. The cardioprotective effect of Trx1 has been demonstrated via cardiac-specific overexpression of Trx1 and dominant negative Trx1. However, the pathophysiological role of endogenous Trx1 has not been defined with a loss-of-function model. To address this, we have generated cardiac-specific Trx1 knockout (Trx1cKO) mice. Methods and results Trx1cKO mice were viable but died with a median survival age of 25.5 days. They developed heart failure, evidenced by contractile dysfunction, hypertrophy, and increased fibrosis and apoptotic cell death. Multiple markers consistently indicated increased oxidative stress and RNA-sequencing revealed downregulation of genes involved in energy production in Trx1cKO mice. Mitochondrial morphological abnormality was evident in these mice. Although heterozygous Trx1cKO mice did not show any significant baseline phenotype, pressure-overload-induced cardiac dysfunction, and downregulation of metabolic genes were exacerbated in these mice. mTOR was more oxidized and phosphorylation of mTOR substrates such as S6K and 4EBP1 was impaired in Trx1cKO mice. In cultured cardiomyocytes, Trx1 knockdown inhibited mitochondrial respiration and metabolic gene promoter activity, suggesting that Trx1 maintains mitochondrial function in a cell autonomous manner. Importantly, mTOR-C1483F, an oxidation-resistant mutation, prevented Trx1 knockdown-induced mTOR oxidation and inhibition and attenuated suppression of metabolic gene promoter activity. Conclusion Endogenous Trx1 is essential for maintaining cardiac function and metabolism, partly through mTOR regulation via Cys1483.

Perm1 regulates cardiac energetics as a downstream target of the histone methyltransferase Smyd1

“…Mammalian expression vector for Perm1 was generated using mouse Perm1 cDNA and pDC316. Reporter plasmids, including ERRE-luc, ERREm-luc, Ndufv1-luc and PGC-1α-luc, were described previously [16,17].…”

Up-regulation of Thioredoxin 1 by aerobic exercise training attenuates endoplasmic reticulum stress and cardiomyocyte apoptosis following myocardial infarction

“…In addition, to explore the mechanism of Trx1 on regulating ER stress, the changes of other signaling molecules need to be detected in the further study. Trx1 could also inhibit mitochondrial dysfunction in the heart, 40 which is one of the causes of cell apoptosis, we speculated Trx1-induced ER stress would be one of the ways to inhibit cell apoptosis.…”

Expression of miRNAs in plasma exosomes derived from patients with atrial fibrillation

“…31,32 Existing studies have indicated that mTOR can affect various biological processes, including cardiomyocyte proliferation, cardiac remodeling, and energy metabolism, in patients with cardiovascular diseases. 33,34 Jin et al also found that miR-496 was able to remedy hypoxia-induced cardiomyocyte apoptosis via PI3k/Akt/mTOR signaling pathways. The above demonstration indicated that MAPK and mTOR signaling pathways play an essential role in the progression of cardiovascular diseases, and at the same time, various miRNAs inside human body play significant a role in the progression of…”

“…mTOR can be affected by multiple factors; including extracellular microenvironments, AMP/ATP energy and oxidative stress, and can exert considerable effects on biological processes such as protein regulation and cell proliferation and apoptosis 31,32. Existing studies have indicated that mTOR can affect various biological processes, including cardiomyocyte proliferation, cardiac remodeling, and energy metabolism, in patients with cardiovascular diseases 33,34. Jin et al also found that miR-496 was able to remedy hypoxia-induced cardiomyocyte apoptosis via PI3k/Akt/mTOR sig-naling pathways.…”