Mitochondria-related miR-574 reduces sperm ATP by targeting ND5 in aging males

Abstract

Couples are delaying childbearing in recent decades. While women experience a notable decrease in oocyte production in their late thirties, the effect of advanced paternal age on reproduction is incompletely understood. Herein, we observed that numerous miRNAs, including miR-574, increased in the sperm of aging males, as indicated by high-throughput sequencing. We demonstrated that miR-574 was upregulated in the sperm of two aging mouse models and was related to inferior sperm motility as an adverse predictor. Moreover, we proved that miR-574 suppressed mitochondrial function and reduced cellular ATP production in GC2 cells. Mechanistically, we demonstrated that miR-574 regulated mitochondrial function by directly targeting mt-ND5. Our study revealed an important role of miR-574 in sperm function in aging males and provided a fresh view to comprehend the aging process in sperm.

Mitochondrial Reactive Oxygen Species (ROS) Production Alters Sperm Quality

“…Accordingly, miRNA content in the seminal plasma significantly changes with age [ 168 ]. By performing high-throughput sequencing of small RNAs in sperm, oocytes and embryos of aged and young mice, it has been demonstrated that there is a differential expression of numerous miRNAs and piRNAs in correlation with the age, most of them involved in embryo development [ 169 ]. A typical example of such a deregulation concerns miR-574, upregulated in the sperm of older mice and significantly related to a decreased sperm motility.…”

“…A typical example of such a deregulation concerns miR-574, upregulated in the sperm of older mice and significantly related to a decreased sperm motility. Interestingly, miR-574 has been shown to suppress mitochondrial function and ATP production by directly targeting the mt-ND5 gene, a typical mitochondrial gene encoding NADH dehydrogenase 5, an essential component of the complex I [ 169 ].…”

miR‐125a‐5p increases cellular DNA damage of aging males and perturbs stage‐specific embryo development via Rbm38‐p53 signaling

“…Excluding differentially expressed miRNAs in oocytes, and overlapping the specific miRNAs in sperm with the differentially expressed miRNAs in embryos, we obtained 33 miRNAs that might contain the contributor of embryo development from the sperm of aging males. Meanwhile, some of these miRNAs were associated with mitochondria, including miR-574, miR-128, let-7b, miR-24, and miR-125a (Ma et al, 2020). In the previous study of our group, we found that miR-574 was upregulated in the sperm of aging males and was related to poor sperm motility as an adverse predictor.…”

“…In a previous study of our group, we found that numerous miRNAs, including miR-574 and miR-125a-5p, were increased in the sperm of aging males. Subsequently, we demonstrated that mitochondriarelated miR-574 could suppress mitochondrial function, reduce cellular ATP production by directly targeting mt-ND5 in aging males, and have an adverse effect on early embryonic development (Ma et al, 2020). Moreover, we found that miR-125a-5p, which is highly conserved between humans and mice (Figure S1a), was also upregulated in both sperm and embryos of aging males (Figure 1a), suggesting that it may play a role in the sperm function or embryo development of aging males.…”

“…In order to investigate the expression patterns of advanced age on reproduction, our group previously performed high-throughput sequencing of small RNAs in sperm, oocytes, and embryos of aged and young mice (Ma et al, 2020). Many miRNAs were found to be differentially expressed in sperm, oocytes, and embryos in aged and young mice.…”