Male Subfertility Induced by Heterozygous Expression of Catalytically Inactive Glutathione Peroxidase 4 Is Rescued in Vivo by Systemic Inactivation of the Alox15 Gene

Brütsch, Simone Hanna; Rademacher, Marlena; Roth, Sophia Regina; Müller, Karin; Eder, Susanne; Viertel, Dagmar; Franz, C.; Kühn, Hartmut; Borchert, Astrid

doi:10.1074/jbc.m116.738930

Cited by 25 publications

(18 citation statements)

References 53 publications

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“…Global knockout of Gpx4 results in early embryonic lethality, while conditional knockout of Gpx4 in specific organs (e.g., myeloid cells) is compatible with survival into adulthood. Conditional knockout models revealed that Gpx4 protects against experimental renal failure (Friedmann Angeli et al, 2014), neurodegenerative diseases (Chen et al, 2015), viral and parasitic infections (Matsushita et al, 2015), male subfertility (Brutsch et al, 2016), atherogenesis (Guo et al, 2008), anemia (Canli et al, 2016), and thrombus formation (Wortmann et al, 2013). Gpx4 depletion resulted in a marked elevation of apoptosis (Ran et al., 2003; Seiler et al, 2008), necroptosis (Canli et al, 2016), and ferroptosis (Friedmann Angeli et al, 2014; Yang et al, 2014b).…”

Section: Discussionmentioning

confidence: 99%

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Kang

Zeng

Zhu

et al. 2018

Cell Host & Microbe

458

327

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Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4 mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.

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Section: Discussionmentioning

confidence: 99%

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Kang

Zeng

Zhu

et al. 2018

Cell Host & Microbe

458

327

View full text Add to dashboard Cite

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“…Whereas GPX4 has multiple molecular functions in the spermatozoa such as regulation of mitochondrial membrane potential, chromatin decondensation and detoxification of phospholipid hydroperoxides [39]. Besides, the moonlighting function of GPX4 (as an ROS metabolizing enzyme and structural protein), it is also responsible for the maintenance of mitochondrial stability and consequent male fertility [40]. GPX4 is also required for differential cell death decision in the testis [41] Sharma et al reported that the levels of GPX4 protein was upregulated in men with high seminal ROS [20].…”

Section: Discussionmentioning

confidence: 99%

Effect of Antioxidant Supplementation on the Sperm Proteome of Idiopathic Infertile Men

et al. 2019

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Antioxidant supplementation in idiopathic male infertility has a beneficial effect on semen parameters. However, the molecular mechanism behind this effect has not been reported. The objective of this study was to evaluate the sperm proteome of idiopathic infertile men pre- and post-antioxidant supplementation. Idiopathic infertile men were provided with oral antioxidant supplementation once daily for a period of 6 months. Of the 379 differentially expressed proteins (DEPs) between pre- and post-antioxidant treatment patients, the majority of the proteins (n = 274) were overexpressed following antioxidant treatment. Bioinformatic analysis revealed the activation of oxidative phosphorylation pathway and upregulation of key proteins involved in spermatogenesis, sperm maturation, binding of sperm, fertilization and normal reproductive function. In addition, the transcriptional factors associated with antioxidant defense system (PPARGC1A) and free radical scavenging (NFE2L2) were predicted to be functionally activated post-treatment. Key DEPs, namely, NDUFS1, CCT3, PRKARA1 and SPA17 validated by Western blot showed significant overexpression post-treatment. Our novel proteomic findings suggest that antioxidant supplementation in idiopathic infertile men improves sperm function at the molecular level by modulating proteins involved in CREM signaling, mitochondrial function and protein oxidation. Further, activation of TRiC complex helped in nuclear compaction, maintenance of telomere length, flagella function, and expression of zona pellucida receptors for sperm–oocyte interaction.

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“…Polyunsaturated fatty acids are known to stimulate ROS generation in human spermatozoa (Aitken, Wingate, De Iuliis, Koppers, & McLaughlin, ), and mammalian spermatozoa are known to possess lipoxygenase activity (Fischer et al, ). The fact that systemic inactivation of the Alox15 gene (encodes 15‐Lipoxygenase) can rescue the infertility phenotype observed in Gpx4 (Glutathione peroxidase 4)‐deficient mice suggests that the lipoxygenase system is somehow involved in the creation of oxidative stress within the male germ line (Brütsch et al, ). This conclusion is reinforced by the recent demonstration that ALOX15 is markedly up‐regulated in response to oxidative stress in round spermatids and in the GC‐2 cell line, whereas pharmacological inhibition of this enzyme reduces both ROS generation and 4‐hydroxynonenal accumulation in these cells (Bromfield et al, ).…”

Section: Physiological Sources Of Ros In Spermatozoamentioning

confidence: 99%

Reactive oxygen species as mediators of sperm capacitation and pathological damage

Aitken

2017

Molecular Reproduction Devel

472

370

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Oxidative stress plays a major role in the life and death of mammalian spermatozoa.These gametes are professional generators of reactive oxygen species (ROS), which appear to derive from three potential sources: sperm mitochondria, cytosolic L-amino acid oxidases, and plasma membrane Nicotinamide adenine dinucleotide phosphate oxidases. The oxidative stress created via these sources appears to play a significant role in driving the physiological changes associated with sperm capacitation through the stimulation of a cyclic adenosine monophosphate/Protein kinase A phosphorylation cascade, including the activation of Extracellular signal regulated kinase-like proteins, massive up-regulation of tyrosine phosphorylation in the sperm tail, as well as the induction of sterol oxidation. When generated in excess, however, ROS can induce lipid peroxidation that, in turn, disrupts membrane characteristics that are critical for the maintenance of sperm function, including the capacity to fertilize an egg.Furthermore, the lipid aldehydes generated as a consequence of lipid peroxidation bind to proteins in the mitochondrial electron transport chain, triggering yet more ROS generation in a self-perpetuating cycle. The high levels of oxidative stress created as a result of this process ultimately damage the DNA in the sperm nucleus; indeed, DNA damage in the male germ line appears to be predominantly induced oxidatively, reflecting the vulnerability of these cells to such stress. Extensive evaluation of antioxidants that protect the spermatozoa against oxidative stress while permitting the normal reduction-oxidation regulation of sperm capacitation is therefore currently being undertaken, and has already proven efficacious in animal models. | INTRODUCTIONCapacitation is a key feature of mammalian sperm cell biology, and was independently reported by Chang (1951) and Austin (1951); its discovery was a sentinel for unwrapping the mysteries of mammalian fertilization.Completion of capacitation provides sperm with a series of behaviours that are essential for the achievement of fertilization, including hyperactivated motility, sperm-zona pellucida recognition, and acrosome exocytosis. Despite being aware of capacitation for more than half a century, the molecular mechanisms that underpin this process at a physiological level are still far from resolved (Aitken & Nixon, 2013). We do know that capacitation involves an efflux of cholesterol from the sperm plasma membrane (Davis, 1981) and a global increase in tyrosine phosphorylation (Visconti et al., 1995). Yet, our understanding of how these elements are controlled is still quite embryonic. In this context, one insight that has emerged in the relatively recent past is that sperm capacitation is a reduction-oxidation (redox)-regulated event, promoted by the de novo generation of low levels of reactive oxygen species (ROS). One of the first scientists to discover this association was the late Claude Gagnon, who published an important paper in 1993 citing the ability of superoxide to...

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Male Subfertility Induced by Heterozygous Expression of Catalytically Inactive Glutathione Peroxidase 4 Is Rescued in Vivo by Systemic Inactivation of the Alox15 Gene

Cited by 25 publications

References 53 publications

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Effect of Antioxidant Supplementation on the Sperm Proteome of Idiopathic Infertile Men

Reactive oxygen species as mediators of sperm capacitation and pathological damage

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