Functional deletion of Txndc2 and Txndc3 increases the susceptibility of spermatozoa to age-related oxidative stress

Smith, Tegan B.; Baker, Mark A.; Connaughton, Haley S.; Habenicht, U.‐F.; Aitken, R. John

doi:10.1016/j.freeradbiomed.2013.05.021

Cited by 67 publications

(42 citation statements)

References 35 publications

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“…Peroxiredoxins (including PRDX5 and PRDX6) have been recently confirmed to be present in human spermatozoa and shown to be potentially capable of protecting the cells from peroxide radical damage (O'Flaherty & de Souza 2011, Gong et al 2012. Furthermore, a knockout mouse lacking the sperm-specific thioredoxins, Txndc2 and Txndc3 (Nme8), has been generated and shown to result in age-dependent changes in the spermatozoa associated with accelerated motility loss, high rates of DNA damage, increases in ROS generation, enhanced formation of lipid aldehyde-protein adducts and impaired protamination of the sperm chromatin (Smith et al 2013). This, together with localisation of PRDX5 to the mitochondrial sheath in human spermatozoa (O'Flaherty &de Souza 2011), leads us to propose that the thioredoxin/peroxiredoxin system may serve as a strategic antioxidative mechanism in equine spermatozoa: cells relying heavily on mitochondria for energy metabolism, and therefore producing high levels of ROS, have a good reason to position their oxidation defences close to the site of ROS release and thus avoid downstream oxidative damage.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the stallion sperm proteome by mass spectrometry

Swegen¹,

Curry²,

Gibb³

et al. 2015

Reproduction

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Stallion spermatozoa continue to present scientific and clinical challenges with regard to the biological mechanisms responsible for their survival and function. In particular, deeper understanding of sperm energy metabolism, defence against oxidative damage and cell-cell interactions should improve fertility assessment and the application of advanced reproductive technologies in the equine species. In this study, we used highly sensitive LC-MS/MS technology and sequence database analysis to identify and characterise the proteome of Percoll-isolated ejaculated equine spermatozoa, with the aim of furthering our understanding of this cell's complex biological machinery. We were able to identify 9883 peptides comprising 1030 proteins, which were subsequently attributed to 975 gene products. Gene ontology analysis for molecular and cellular processes revealed new information about the metabolism, antioxidant defences and receptors of stallion spermatozoa. Mitochondrial proteins and those involved in catabolic processes constituted dominant categories. Several enzymes specific to b-oxidation of fatty acids were identified, and further experiments were carried out to ascertain their functional significance. Inhibition of carnitine palmitoyl transferase 1, a rate-limiting enzyme of b-oxidation, reduced motility parameters, indicating that b-oxidation contributes to maintenance of motility in stallion spermatozoa.

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Section: Discussionmentioning

confidence: 99%

Investigation of the stallion sperm proteome by mass spectrometry

Swegen¹,

Curry²,

Gibb³

et al. 2015

Reproduction

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“…Work in mice has shown that deletion of the thioredoxin domains in sperm increases their age-related susceptibility to oxidative stress-induced phenotypes [60]. Literature on this gene is limited and indicates expression is primarily restricted to testis and respiratory epithelial cells [60, 61]. However, if expression of NME8 was observed in the brain, the association between NME8 and AD risk could be explained by variation that modifies its antioxidant action and subsequently alters the level of oxidative stress.…”

Section: Identification Of Load Genes By Genome-wide Association Studiesmentioning

confidence: 99%

Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways

2014

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Late-onset Alzheimer’s disease (LOAD) is a devastating neurodegenerative disease with no effective treatment or cure. In addition to APOE, recent large genome-wide association studies have identified variation in over 20 loci that contribute to disease risk: CR1, BIN1, INPP5D, MEF2C, TREM2, CD2AP, HLA-DRB1/HLA-DRB5, EPHA1, NME8, ZCWPW1, CLU, PTK2B, PICALM, SORL1, CELF1, MS4A4/MS4A6E, SLC24A4/RIN3,FERMT2, CD33, ABCA7, CASS4. In addition, rare variants associated with LOAD have also been identified in APP, TREM2 and PLD3 genes. Previous research has identified inflammatory response, lipid metabolism and homeostasis, and endocytosis as the likely modes through which these gene products participate in Alzheimer’s disease. Despite the clustering of these genes across a few common pathways, many of their roles in disease pathogenesis have yet to be determined. In this review, we examine both general and postulated disease functions of these genes and consider a comprehensive view of their potential roles in LOAD risk.

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“…In cases of oxidative stress, glucose 6-phosphate dehydrogenase, generator of NADPH, is inactivated and thus the amount of NADPH is rapidly depleted and in consequence this reducing equivalent is no longer available [114]. Recently, it was reported that aging mice lacking SPTRX1 and SPTRX2 are subfertile [115]. This findings support the need for an intact TRX system to assure fertility.…”

Section: Introductionmentioning

confidence: 99%

Peroxiredoxins: hidden players in the antioxidant defence of human spermatozoa

O’Flaherty

2014

Basic Clin. Androl.

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Spermatozoon is a cell with a precious message to deliver: the paternal DNA. Its motility machinery must be working perfectly and it should be able to acquire fertilizing ability in order to accomplish this mission. Infertility touches 1 in 6 couples worldwide and in half of the cases the causes can be traced to men. A variety of conditions such as infections of the male genital tract, varicocele, drugs, environmental factors, diseases, smoking, etc., are associated with male infertility and a common feature among them is the oxidative stress in semen that occurs when reactive oxygen species (ROS) are produced at high levels and/or when the antioxidant systems are decreased in the seminal plasma and/or spermatozoa. ROS-dependent damage targets proteins, lipids, and DNA, thus compromising sperm function and survival. Elevated ROS in spermatozoa are associated with DNA damage and decreased motility. Paradoxically, ROS, at very low levels, regulate sperm activation for fertilization. Therefore, the regulation of redox signaling in the male reproductive tract is essential for fertility. Peroxiredoxins (PRDXs) play a central role in redox signaling being both antioxidant enzymes and modulators of ROS action and are essential for pathological and physiological events. Recent studies from our lab emphasize the importance of PRDXs in the protection of spermatozoa as infertile men have significant low levels of PRDXs in semen and with little enzymatic activity available for ROS scavenging. The relationships between sperm DNA damage, motility and lipid peroxidation and high levels of thiol-oxidized PRDXs suggest the enhanced susceptibility of spermatozoa to oxidative stress and further support the importance of PRDXs in human sperm physiology. This review aims to characterize PRDXs, hidden players of the sperm antioxidant system and highlight the central role of PRDXs isoforms in the protection against oxidative stress to assure a proper function and DNA integrity of human spermatozoa.

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Functional deletion of Txndc2 and Txndc3 increases the susceptibility of spermatozoa to age-related oxidative stress

Cited by 67 publications

References 35 publications

Investigation of the stallion sperm proteome by mass spectrometry

Investigation of the stallion sperm proteome by mass spectrometry

Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways

Peroxiredoxins: hidden players in the antioxidant defence of human spermatozoa

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