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Decreased Klotho Expression Causes Accelerated Decline of Male Fecundity through Oxidative Injury in Murine Testis
Ya-Yun Wang1, Ying-Hung Lin1, Vin-Cent Wu2,3
1Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Abstract:
Oxidative stress is the etiology for 30-80% of male patients affected by infertility, which is a major health problem worldwide. Klotho protein is an aging suppressor that functions as a humoral factor modulating various cellular processes including antioxidation and anti-inflammation, and its dysregulation leads to human pathologies. Male mice lacking Klotho are sterile, and decreased Klotho levels in the serum are observed in men suffering from infertility with lower sperm counts. However, the mechanism by which Klotho maintains healthy male fertility remains unclear. Klotho haplodeficiency (Kl+) accelerates fertility reduction by impairing sperm quality and spermatogenesis in Kl+/- mice. Testicular proteomic analysis revealed that loss of Klotho predominantly disturbed oxidation and the glutathione-related pathway. We further focused on the glutathione-S-transferase (GST) family which counteracts oxidative stress in most cell types and closely relates with fertility. Several GST proteins, including GSTP1, GSTO2, and GSTK1, were significantly downregulated, which subsequently resulted in increased levels of the lipid peroxidation product 4-hydroxynonenal and apoptosis in murine testis with low or no expression of Klotho. Taken together, the loss of one Kl allele accelerates male fecundity loss because diminished antioxidant capability induces oxidative injury in mice. This is the first study that highlights a connection between Klotho and GST proteins.
Insights
Klotho protein deficiency accelerates male infertility by impairing sperm quality and spermatogenesis. This occurs due to reduced antioxidant capacity, leading to oxidative stress and damage in the testes.
Area of Science:
- Reproductive biology
- Aging research
- Molecular endocrinology
Background:
- Oxidative stress is a significant factor in male infertility.
- Klotho protein, an aging suppressor, plays a role in cellular antioxidation.
- Klotho dysregulation is linked to pathologies, and Klotho deficiency causes sterility in male mice.
Purpose of the Study:
- To elucidate the mechanism by which Klotho protein maintains male fertility.
- To investigate the impact of Klotho haplodeficiency on male reproductive health.
- To identify the molecular pathways affected by Klotho loss in the male reproductive system.
Main Methods:
- Analysis of male mice with Klotho haplodeficiency (Kl+/-).
- Testicular proteomic analysis to identify disturbed pathways.
- Quantification of glutathione-S-transferase (GST) protein levels and lipid peroxidation products.
Main Results:
- Klotho haplodeficiency accelerates fertility reduction by impairing sperm quality and spermatogenesis.
- Loss of Klotho predominantly disturbed oxidation and the glutathione-related pathway.
- Downregulation of GST proteins (GSTP1, GSTO2, GSTK1) led to increased 4-hydroxynonenal and apoptosis in testes.
Conclusions:
- Loss of one Klotho allele accelerates male fecundity loss due to diminished antioxidant capability and induced oxidative injury.
- This study reveals a novel connection between Klotho protein and glutathione-S-transferase proteins in maintaining male fertility.
- Klotho is crucial for counteracting oxidative stress in the male reproductive system.
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