CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Thioredoxin system in redox regulation of cell signalling

Reactive oxygen species (ROS) are generally considered responsible of the damage inflicted to biological molecules by oxidative stress. However, more recently, oxidant species at relatively low concentrations are considered to act as second messengers in cellular events depending on cytokines and growth factors. In the cell, the thiol redox state is controlled by the thioredoxin and glutathione systems, present both in mitochondria and cytosol, and able to modulate the concentration of hydrogen peroxide (see Figure).

 

The thioredoxin system, comprising NADPH, thioredoxin reductase (TrxR), and thioredoxin (Trx) plays a critical role in regulating cell viability and proliferation.

Results and Perspectives

Following our previous observations on the presence of a glutathione-independent disulfide reductase activity in mitochondria we isolated and purified the mitochondrial isoform of thioredoxin reductase (TrxR2) and found it different from the cytosolic isoform (TrxR1). Mitochondrial thioredoxin reductase has different molecular weight from the cytosolic isoform and also exhibits different chromatographic and kinetic behaviour, different sequence and isoelectric point. However, similarly to TrxR1 possess a C-terminal sequence gly-cys-Secys-gly characterized by the selenol residue. Thioredoxin reductase delivers electrons to thioredoxin that, in turn, reduces peroxiredoxins which rapidly regulates the level of hydrogen peroxide. The thioredoxin system plays a pivotal role in the redox regulation of signalling molecules and transcription factors. A well known example is the redox regulation of ASK1 by thioredoxin acting in this way as a negative regulator of apoptosis. In mitochondria, among the targets of thioredoxin reductase we identified the enzyme protein disulfide isomerase (PDI) found to be present essentially at the level of the outer mitochondrial membrane. Presently, we are exploring the thioredoxin system-dependent redox processes in hepatic stellate cells with particular reference to the liver fibrogenesis.

Publications

  • Rigobello MP, Gandin V, Folda A, Rundlöf AK, Fernandes AP, Bindoli A, Marzano C, Björnstedt M (2009) Treatment of human cancer cells with selenite or tellurite in combination with auranofin enhances cell death due to redox shift. Free Radic. Biol. Med. 47:710-21.
  • Bindoli A, Fukuto JM, Forman HJ (2008) Thiol chemistry in peroxidase catalysis and redox signaling. Antioxid. Redox Signal. 10:1549-64.
  • Rigobello MP, Vianello F, Folda A, Roman C, Scutari G, Bindoli A (2006) Differential effect of calcium ions on the cytosolic and mitochondrial thioredoxin reductase. Biochem. Biophys. Res. Commun. 343:873-8.
  • Rigobello MP, Folda A, Scutari G, Bindoli A (2005) The modulation of thiol redox state affects the production and metabolism of hydrogen peroxide by heart mitochondria. Arch. Biochem. Biophys. 441:112-22.

Collaborations

  • Mikael Björnstedt, Aristi P. Fernandes, Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Karolisnka University Hospital Huddinge, Stockholm, Sweden.
  • Christine Marzano, Valentina Gandin, Dipartimento di Scienze Farmaceutiche, Università di Padova, Padova, Italy.
  • Mario Plebani, Guido Scutari, Scuola di Specializzazione in Biochimica Clinica, Università di Padova, Padova, Italy.
  • Anna Maria Brunati, Dipartimento di Chimica Biologica, Università di Padova, Padova, Italy.

 

PI photo

Alberto Bindoli

Contact information

email  E-mail

email  049 8276138

Participating staff

Maria Pia Rigobello
Assistant professor

Guido Scutari
Associate professor

Alessandra Folda
Laureate technician