Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice

Kaczmarek, K.; Studencka, Maja; Meinhardt, Andreas; Wieczerzak, Krzysztof; Thoms, Sven; Engel, Wolfgang; Grzmil, Paweł

doi:10.1091/mbc.e09-12-0993

Cited by 28 publications

(32 citation statements)

References 70 publications

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“…Apoptosis is a mode of cellular death that induces a series of cellular morphological and biochemical alterations leading to cell suicide [58,59]. Chen et al [60] showed a significant correlation between apoptosis and male infertility, and this relationship was also observed in a mouse model [61]. In the present study, an increased apoptotic rate of sperm was observed in the Cd-treated group.…”

Section: Discussionsupporting

confidence: 71%

The Protective Effects of Melatonin Against Oxidative Stress and Inflammation Induced by Acute Cadmium Exposure in Mice Testis

Luo

et al. 2015

Biol Trace Elem Res

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Cadmium (Cd) is widely used in daily life and was recently recognized as a possible source of human toxicity due to its ability to accumulate in organs. Previous studies have shown that Cd exposure may cause testicular toxicity through oxidative stress and an inflammatory effect. Melatonin has been demonstrated to be an effective anti-oxidant and has an anti-inflammatory effect. The aim of the present study was to investigate the toxicological effects of Cd on reproduction in male mice and the potential protective action of melatonin against these adverse effects. Adult male mice were injected intraperitoneally with Cd at a dose of 2 mg/kg body weight per day for seven consecutive days with or without melatonin pretreatment. Sex organ weight, sperm parameters including sperm quality, apoptosis, acrosome integrity, mitochondrial membrane potential, testicular morphology, serum sex hormone, inflammatory status, and oxidative stress were evaluated. The results showed that significant adverse effects were observed in the male reproductive system after Cd exposure, including alterations in sperm parameters, increased DNA damage, and sex hormone disturbance. Acute Cd exposure also significantly increased malondialdehyde (MDA) contents, decreased glutathione (GSH) and superoxide dismutase (SOD) activities, and upregulated levels of the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β), in the testis. In contrast, melatonin pretreatment significantly alleviated these toxic effects, and its mechanism may involve inhibiting MDA level, restoring GSH and SOD activities, and reducing the upregulation of TNF-α and IL-1β. Our data suggest that oxidative stress and inflammation are involved in Cd-induced toxicity in the male reproductive system and that co-administration of melatonin exerts a protective effect against Cd-induced male reproductive toxicity.

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Section: Discussionsupporting

confidence: 71%

The Protective Effects of Melatonin Against Oxidative Stress and Inflammation Induced by Acute Cadmium Exposure in Mice Testis

Luo

et al. 2015

Biol Trace Elem Res

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“…Consistent with the lower apoptotic rate of germ cells at 15 dpn, the RNA-seq analysis of Fxrα −/− testis identified several genes known to be involved in germ cell apoptotic processes such as Pxt1 (Kaczmarek et al., 2011), Bak1 (Kratz et al., 2011), and Caspase-6 (Omezzine et al., 2003), which were validated by qPCR analysis (Figure 6A). Caspase-6 protein accumulation was lower in Fxrα −/− than in WT males (Figure 6B).…”

Section: Resultsmentioning

confidence: 68%

The Bile Acid Nuclear Receptor FXRα Is a Critical Regulator of Mouse Germ Cell Fate

et al. 2017

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SummarySpermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxrα−/− mice, we describe unexpected roles of FXRα on germ cell physiology independent of its effects on somatic cells. FXRα helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRα regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRα controls the expression of the pluripotency marker Lin28 in the germ cells.

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“…PXT1, which binds tightly to all five prosurvival proteins (Figure 2), is a peroxisomal protein that promotes apoptosis in sperm cells. The BH3 motif we predict was recognized by Kaczmarek et al, who demonstrated that deleting this region in PXT1 significantly reduces PXT1-induced apoptosis [38]. The channel protein TRPM7 has pro-apoptotic function mediated by caspases, which cleave the kinase domain of TRPM7 from its transmembrane channel domain.…”

Section: Discussionmentioning

confidence: 89%

Genome-Wide Prediction and Validation of Peptides That Bind Human Prosurvival Bcl-2 Proteins

2014

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Programmed cell death is regulated by interactions between pro-apoptotic and prosurvival members of the Bcl-2 family. Pro-apoptotic family members contain a weakly conserved BH3 motif that can adopt an alpha-helical structure and bind to a groove on prosurvival partners Bcl-xL, Bcl-w, Bcl-2, Mcl-1 and Bfl-1. Peptides corresponding to roughly 13 reported BH3 motifs have been verified to bind in this manner. Due to their short lengths and low sequence conservation, BH3 motifs are not detected using standard sequence-based bioinformatics approaches. Thus, it is possible that many additional proteins harbor BH3-like sequences that can mediate interactions with the Bcl-2 family. In this work, we used structure-based and data-based Bcl-2 interaction models to find new BH3-like peptides in the human proteome. We used peptide SPOT arrays to test candidate peptides for interaction with one or more of the prosurvival proteins Bcl-xL, Bcl-w, Bcl-2, Mcl-1 and Bfl-1. For the 36 most promising array candidates, we quantified binding to all five human receptors using direct and competition binding assays in solution. All 36 peptides showed evidence of interaction with at least one prosurvival protein, and 22 peptides bound at least one prosurvival protein with a dissociation constant between 1 and 500 nM; many peptides had specificity profiles not previously observed. We also screened the full-length parent proteins of a subset of array-tested peptides for binding to Bcl-xL and Mcl-1. Finally, we used the peptide binding data, in conjunction with previously reported interactions, to assess the affinity and specificity prediction performance of different models.

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Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice

Abstract: The overexpression of PXT1 in mouse testis leads to germ cell apoptosis and male infertility. The PXT1 protein contains a functional BH3-motif. PXT1 protein interacts with BAT3, and BAT3 is able to protect cells from PXT1-induced apoptosis.

Cited by 28 publications

References 70 publications

The Protective Effects of Melatonin Against Oxidative Stress and Inflammation Induced by Acute Cadmium Exposure in Mice Testis

The Protective Effects of Melatonin Against Oxidative Stress and Inflammation Induced by Acute Cadmium Exposure in Mice Testis

The Bile Acid Nuclear Receptor FXRα Is a Critical Regulator of Mouse Germ Cell Fate

Genome-Wide Prediction and Validation of Peptides That Bind Human Prosurvival Bcl-2 Proteins

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