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Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells.

ABSTRACT: Disruption of the nursery function in Sertoli cells (SCs) by reducing lactate production, a preferred energy substrate for developed germ cells (spermatocytes and spermatids), is tightly associated with spermatogenic failure such as SC-only syndrome (SCOS). However, whether this complicated pathogenesis is regulated by certain miRNAs at the post-transcriptional level remain fascinating but largely unknown. Here we show for the first time that mmu-miR-320-3p was exclusively expressed in murine SCs and this expression was significantly induced in busulphan-treated murine testis. The most efficient stimulatory germ cell types for the induction of apoptosis-elicited mmu-miR-320-3p expression were meiotic spermatocytes and haploid spermatids. Functionally, forced expression of the exogenous mmu-miR-320-3p in SCs compromises male fertility by causing oligozoospermia and defection of sperm mobility. Mechanistically, mmu-miR-320-3p negatively regulates lactate production of SCs by directly inhibiting glucose transporter 3 (GLUT3) expression. Thus, dysregulation of mmu-miR-320-3p/GLUT3 cascade and consequently of lactate deficiency may be a key molecular event contributing the germ cell loss by SC dysfunction. Future endeavor in the continuous investigation of this important circulating miRNA may shed novel insights into epigenetic regulation of SCs nursery function and the etiology of azoospermia, and offers novel therapeutic and prognostic targets for SCOS.

SUBMITTER: Zhang LL

PROVIDER: S-EPMC6148074 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells.

Zhang Li-Li LL Ma Jing J Yang Bo B Zhao Jie J Yan Bin-Yuan BY Zhang Yuan-Qiang YQ Li Wei W

Cell death & disease 20180920 10

Disruption of the nursery function in Sertoli cells (SCs) by reducing lactate production, a preferred energy substrate for developed germ cells (spermatocytes and spermatids), is tightly associated with spermatogenic failure such as SC-only syndrome (SCOS). However, whether this complicated pathogenesis is regulated by certain miRNAs at the post-transcriptional level remain fascinating but largely unknown. Here we show for the first time that mmu-miR-320-3p was exclusively expressed in murine SC ...[more]

PMID: 30237478

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Project description:BackgroundAlthough varicocele is considered to be one of the leading causes of male infertility, the precise mechanism underlying how varicocele leads to male infertility is not completely understood. We found the lactate concentration on the varicocele side of the patients was decreased compare with peripheral venous blood. In the testicles, the lactate produced by the sertoli cells through the glycolysis pathway provides most of the energy needed for spermatogenesis, the reduction of lactate will affect spermatogenesis. The objective of this study was to investigate the mechanism of this abnormal energy metabolism phenomenon in varicocele.MethodsIn this study, we collected the testicular tissue from patients with varicocele, the glycolysis related proteins PHGDH was identified by iTRAQ proteomics technology. Experimental rat varicocele model was constructed according to our new clip technique, the mRNA and protein expression levels of PHGDH were examined with qRT-PCR and Western blotting. We constructed a sertoli cell of PHGDH down-regulation model, and then detected the glucose consumption, LDH activities and lactate production in the sertoli cells. Western blot was conducted to investigate the effects of PHGDH on the expression of phosphoserine phosphatase (PSPH) and Pyruvate kinase M2 (PKM2). Flow cytometry was used to detect the cell apoptosis and cell cycle in sertoli cells.ResultsThe results showed that testicular protein PHGDH was down-regulated in patients with varicocele and in experimental rat varicocele model. Down-regulation of PHGDH in sertoli cells significantly decreased the glucose consumption, LDH activities and lactate production in the sertoli cells, indicating that the low expression of PHGDH ultimately led to a decrease in lactate production by affecting the glycolysis. The Western blot results showed that the down-regulation of PHGDH significantly reduced the expression of pathway protein PSPH and PKM2, leading to the reduction of lactate production. Moreover, PHGDH knockdown can promote apoptosis and inhibit cell cycle to affect cell growth.ConclusionsOverall, we conformed that varicocele lead to the decreasing of testis lactate production. Down-regulation of PHGDH in sertoli cells may mediate the process of abnormal glucose metabolism. Our study provide new insight into the mechanisms underlying metabolism-associated male infertility and suggests a novel therapeutic target for male infertility.

Dataset Information

Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells.

Publications

Interference with lactate metabolism by mmu-miR-320-3p via negatively regulating GLUT3 signaling in mouse Sertoli cells.

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