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Open Access item The Characterization of the Caenorhabditis elegans Mitochondrial Thioredoxin System Uncovers an Unexpected Protective Role of Thioredoxin Reductase 2 in β-Amyloid Peptide Toxicity

Authors:Cacho-Valadez, Briseida
Muñoz-Lobato, Fernando
Pedrajas, José R.
Cabello, Juan
Fierro-González, Juan Carlos
Navas, Plácido
Swoboda, Peter
Link, Chris D.
Miranda-Vizuete, Antonio
Keywords:Mitochondrial thioredoxin system, Caenorhabditis elegans, Thioredoxin 2, Thioredoxin reductase 2, Protein, Oxygen, Apoptotic, Alzheimer's disease
Issue Date:15-Feb-2012
Publisher:Mary Ann Liebert, Inc
Citation:Antioxidants and Redox Signalling
Abstract:Aim: Functional in vivo studies on the mitochondrial thioredoxin system are hampered by the embryonic or larval lethal phenotypes displayed by murine or Drosophila knock-out models. Thus, the access to alternative metazoan knock-out models for the mitochondrial thioredoxin system is of critical importance. Results: We report here the characterization of the mitochondrial thioredoxin system of Caenorhabditis elegans that is composed of the genes trx-2 and trxr-2. We demonstrate that the proteins thioredoxin 2 (TRX-2) and thioredoxin reductase 2 (TRXR-2) localize to the mitochondria of several cells and tissues of the nematode and that trx-2 and trxr-2 are upregulated upon induction of the mitochondrial unfolded protein response. Surprisingly, C. elegans trx-2 (lof ) and trxr-2 (null) single and double mutants are viable and display similar growth rates as wild-type controls. Moreover, the lack of the mitochondrial thioredoxin system does not affect longevity, reactive oxygen species production or the apoptotic program. Interestingly, we found a protective role of TRXR-2 in a transgenic nematode model of Alzheimer's disease (AD) that expresses human β-amyloid peptide and causes an age-dependent progressive paralysis. Hence, trxr-2 downregulation enhanced the paralysis phenotype, while a strong decrease of β-amyloid peptide and amyloid deposits occurred when TRXR-2 was overexpressed. Innovation: C. elegans provides the first viable metazoan knock-out model for the mitochondrial thioredoxin system and identifies a novel role of this system in β-amyloid peptide toxicity and AD. Conclusion: The nematode strains characterized in this work make C. elegans an ideal model organism to study the pathophysiology of the mitochondrial thioredoxin system at the level of a complete organism. Antioxid. Redox Signal. 00, 000–000.
Description:48 páginas, 8 figuras. Material suplementario y métodos 19 páginas, 6 figuras, 3 tablas.
Publisher version (URL):http://dx.doi.org/10.1089/ars.2011.4265
E-ISSNmetadata.dc.identifier.doi = DOI:1557-7716
Appears in Collections:(CABD) Artículos
(IBIS) Artículos

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