Abstract
The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.
Highlights
Thioredoxin and Glutaredoxin Systems in Redox BiologyThe thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) [1,2]
Superoxide dismutase and catalase have previously been described as being altered in Friedreich’s ataxia (FRDA) [64,65] and we have found a deficiency in the expression of cytosolic CuZnSOD and mitochondrial Manganese superoxide dismutase (MnSOD) [60], which is in agreement with previous studies demonstrating that the up-regulation of MnSOD fails to occur in FRDA fibroblasts when they are exposed to iron [64,65]
The role of thioredoxin family proteins remains an unexplored field in FRDA, but further efforts should be made in order to clarify the specific implications of TRXs and GRXs malfunction and, in particular, their involvement in Fe-S clusters or their contribution with frataxin in Fe-S cluster biogenesis in mitochondria and how they participate to the appropriate function of IRPs and iron metabolism, all of which are crucial in the physiopathology of FRDA [144]
Summary
The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) [1,2]. GLRX proteins react via monothiol or dithiol mechanisms using one or two cysteines in their Cys–Pro–Tyr–Cys active site [23,24,25,26] They contribute to controlling the levels of internal disulfide bridges in proteins (by means of the di-thiol catalyzed mechanism) and reducing S-glutathionylation (using the mono-thiol mechanism) under conditions of oxidative stress [21,27] (Figure 1). The translocation of the transcription factor NRF2 to the nucleus depends on the cytosolic levels of GSH (which controls the interaction between NRF2 and its modulator Kelch-like ECH-associated protein 1 (Keap1)) and the nuclear TRX1 The translocation of the transcription factor NRF2 to the nucleus depends on the cytosolic levels of GSH (which controls the interaction between NRF2 and its modulator Kelch-like ECH-associated protein 1 (Keap1)) and the nuclear TRX1 (which promotes NRF2-DNA binding). The maintenance of redox homeostasis in cells requires the restoration of the redox status of antioxidant proteins such as cytosolic TRX1, which are maintained in a reduced form by the GSH system thanks to the action of GLRXs [48,49] or by the action of thioredoxin reductase 1 (TRXRD1), it has been demonstrated that TRXRD1 is not absolutely required to maintain reduced TRX1 levels in cells [50]
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