Reproductive biology and endocrinology : RB&E · 2025
Upregulation of miR-151a-5p in high DFI sperm induces DNA damage and mitochondrial dysfunction by targeting INPP4B and VAMP1.
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Lin Xiaoting, Guo Jiaming, Wang Xibo, Xiao Xi, Sun Jie, Ding Wen, Peng Yun, Yan Hongli
Аннотация
OBJECTIVE: To explore the potential the role of miR-151a-5p in sperm dysfunction and its association with DNA fragmentation, mitochondrial dysfunction, and male infertility.
METHODS: Sperm samples with high DNA fragmentation were collected, and miR-151a-5p expression was measured using quantitative polymerase chain reaction. GC-2 cells were transfected with miR-151a-5p mimics to assess its effects on DNA damage, apoptosis, mitochondrial function, and reactive oxygen species levels. RNA sequencing, RNA pull-down, and bioinformatics analyses were used to identify the direct target genes of miR-151a-5p. Dual-luciferase reporter assays confirmed the binding of miR-151a-5p to the 3' untranslated regions of INPP4B and VAMP1. Knockdown of these genes was performed to validate their roles in miR-151a-5p-induced effects. In vivo experiments were conducted by injecting miR-151a-5p mimics into mouse zygotes to examine the impact on embryo development.
RESULTS: miR-151a-5p was significantly upregulated in sperm with high DNA fragmentation and negatively correlated with sperm motility and viability. Overexpression of miR-151a-5p in GC-2 cells was associated with increased DNA damage, apoptosis, mitochondrial dysfunction, and elevated reactive oxygen species. RNA sequencing and bioinformatics analyses suggested INPP4B and VAMP1 as direct targets of miR-151a-5p. Dual-luciferase assays confirmed that miR-151a-5p binds to their 3' untranslated regions, inhibiting their expression at both the messenger RNA and protein levels. Knockdown of INPP4B or VAMP1 partially reproduced the cellular changes observed with miR-151a-5p overexpression. In vivo, microinjection of miR-151a-5p mimics into mouse zygotes exerted only mild effects on embryo development, indicating a possible contribution of miR-151a-5p primarily through sperm dysfunction.
CONCLUSIONS: miR-151a-5p may contributes to sperm dysfunction by targeting INPP4B and VAMP1, linking DNA fragmentation with mitochondrial and genomic instability. This study offers additional insights into the molecular mechanisms underlying male infertility.
METHODS: Sperm samples with high DNA fragmentation were collected, and miR-151a-5p expression was measured using quantitative polymerase chain reaction. GC-2 cells were transfected with miR-151a-5p mimics to assess its effects on DNA damage, apoptosis, mitochondrial function, and reactive oxygen species levels. RNA sequencing, RNA pull-down, and bioinformatics analyses were used to identify the direct target genes of miR-151a-5p. Dual-luciferase reporter assays confirmed the binding of miR-151a-5p to the 3' untranslated regions of INPP4B and VAMP1. Knockdown of these genes was performed to validate their roles in miR-151a-5p-induced effects. In vivo experiments were conducted by injecting miR-151a-5p mimics into mouse zygotes to examine the impact on embryo development.
RESULTS: miR-151a-5p was significantly upregulated in sperm with high DNA fragmentation and negatively correlated with sperm motility and viability. Overexpression of miR-151a-5p in GC-2 cells was associated with increased DNA damage, apoptosis, mitochondrial dysfunction, and elevated reactive oxygen species. RNA sequencing and bioinformatics analyses suggested INPP4B and VAMP1 as direct targets of miR-151a-5p. Dual-luciferase assays confirmed that miR-151a-5p binds to their 3' untranslated regions, inhibiting their expression at both the messenger RNA and protein levels. Knockdown of INPP4B or VAMP1 partially reproduced the cellular changes observed with miR-151a-5p overexpression. In vivo, microinjection of miR-151a-5p mimics into mouse zygotes exerted only mild effects on embryo development, indicating a possible contribution of miR-151a-5p primarily through sperm dysfunction.
CONCLUSIONS: miR-151a-5p may contributes to sperm dysfunction by targeting INPP4B and VAMP1, linking DNA fragmentation with mitochondrial and genomic instability. This study offers additional insights into the molecular mechanisms underlying male infertility.