Reduction of SLC7A11 and GPX4 Contributing to Ferroptosis in Sperm from Asthenozoospermia Individuals

Hao, Xiaochen; Wang, Hong; Cui, Fang; Yang, Zihan; Liu, Ye; Huang, Run; Meng, Jiangping

doi:10.1007/s43032-022-01004-y

Cited by 19 publications

(4 citation statements)

References 55 publications

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“…Notably, spermatocyte-specific Gpx4 deletion in mice causes severe testicular atrophy, reduced spermatogenesis, germ cell death, and infertility ( Imai et al, 2009 ), highlighting its importance in male reproductive biology. Reduced GPX4 activity is also observed in the sperm of infertile patients, emphasizing its role in human spermatogenesis ( Imai et al, 2001 ; Foresta et al, 2002 ; Hao et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis

Radaelli,

Assenmacher,

Verrelle

et al. 2023

eLife

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Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis

Radaelli,

Assenmacher,

Verrelle

et al. 2023

eLife

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show abstract

“…GPX4 is a selenium protein expressed by cells of various organs, and its synthesis and activity are affected by selenium and GSH levels [ 78 , 79 ]. Studies have shown treatment of germ cells with selenium can increase GPX4 expression, maintain spermatozoal motility, and increase germ cell proliferation, indicating the xCT/GPX4 system plays a role in male infertility [ 80 , 81 ]. In another study, sperm specimens from smoking patients showed decreased spermatozoal motility and decreased GPX4 expression [ 82 ].…”

Section: The Role Of Ferroptosis In the Testismentioning

confidence: 99%

Emerging roles of ferroptosis in male reproductive diseases

Yuan,

Sun,

et al. 2023

Cell Death Discov.

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Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation that leads to excessive lipid peroxidation in different cells. Ferroptosis is distinct from other forms of cell death and is associated with various diseases. Iron is essential for spermatogenesis and male reproductive function. Therefore, it is not surprising that new evidence supports the role of ferroptosis in testicular injury. Although the molecular mechanism by which ferroptosis induces disease is unknown, several genes and pathways associated with ferroptosis have been linked to testicular dysfunction. In this review, we discuss iron metabolism, ferroptosis, and related regulatory pathways. In addition, we analyze the endogenous and exogenous factors of ferroptosis in terms of iron metabolism and testicular dysfunction, as well as summarize the relationship between ferroptosis and male reproductive dysfunction. Finally, we discuss potential strategies to target ferroptosis for treating male reproductive diseases and provide new directions for preventing male reproductive diseases.

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“…PM2.5 interferes with the metabolism of glutathione and purines, causing redox imbalance and the excessive accumulation of lipid peroxides; this induces the DNA damage response and cell cycle arrest in mice and leads to iron overload and ferroptosis, ultimately causing the impaired proliferation and decreased function of spermatogonia (Shi et al 2022 ). Additionally, clinical studies have confirmed that the reduced expression of GPX4 and SLC7A11 and increased ferroptosis are associated with impaired sperm function in individuals with asthenozoospermia (Hao et al 2023 ). In contrast, the relationship between impaired spermatogenic function and ferroptosis in juveniles due to PM2.5 has been little studied.…”

Section: Introductionmentioning

confidence: 95%

PM 2.5 juvenile exposure–induced spermatogenesis dysfunction by triggering testes ferroptosis and antioxidative vitamins intervention in adult male rats

Liu,

Ai,

Xiao

et al. 2023

Environ Sci Pollut Res

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PM2.5 derived from automobile exhaust can cause reproductive impairment in adult males, but the toxic effects of PM2.5 exposure on reproductive function in juvenile male rats and its relationship with ferroptosis have not been reported. In this paper, 30-day-old juvenile male Sprague-Dawley (SD) rats were divided into four groups (blank control, vitamin control, PM2.5, and PM2.5+Vitamin). The blank control group was fed normally, and the vitamin control group was given intragastric administration of vitamins in addition to normal feeding. PM2.5 was administered via tracheal intubation. When the rats were treated for 4 weeks until reaching the period of sexual maturity. A mating test was performed first, and then their testicular and epididymal tissues were studied. Compared with control rats, juvenile male rats exposed to PM2.5 showed a decreased sperm count and fertility rate, redox imbalance, damaged mitochondria, a metabolic disorder of intracellular iron ions, and a significant rise in ferroptosis during the period of sexual maturity. After antioxidative vitamins intervention, the redox imbalance, metabolic disorder of intracellular iron ions, and ferroptosis were all alleviated, leading to the following conclusions: after being exposed to PM2.5 from automobile exhaust, male juvenile rats during the period of sexual maturity have significantly decreased reproductive function. The reproductive toxicity of PM2.5 is closely related to oxidative stress and ferroptosis. In addition, ferroptosis decreases and reproductive function is recovered to some degree after antioxidative vitamins intervention. Graphical abstract

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Reduction of SLC7A11 and GPX4 Contributing to Ferroptosis in Sperm from Asthenozoospermia Individuals

Cited by 19 publications

References 55 publications

Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis

Mitochondrial defects caused by PARL deficiency lead to arrested spermatogenesis and ferroptosis

Emerging roles of ferroptosis in male reproductive diseases

PM 2.5 juvenile exposure–induced spermatogenesis dysfunction by triggering testes ferroptosis and antioxidative vitamins intervention in adult male rats

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