Abstract
Ubiquinol-cytochrome-c reductase core protein 2 (UQCRC2) is a component of ubiquinol-cytochrome c reductase complex that is known to correlate with male fertility via spermatogenesis. Simultaneously, nutlin-3a is a small molecule antagonist of mouse double minute 2 repressor (MDM2), activate p53 and induce apoptosis responsible for spermatogenesis. To date, however there are no known effects of nutlin-3a on reproduction. Therefore, present study was designed to investigate the effect of nutlin-3a on male fertility via UQCRC2. In this in vitro trial with mice spermatozoa, we utilized CASA, CTC staining, ATP assay, western blotting, and IVF to measure the main study outcome. The short-term exposure of spermatozoa in nutlin-3a decreases sperm motion kinematics, intracellular ATP production, capacitation, the acrosome reaction, UQCRC2, and tyrosine phosphorylation (TYP) of sperm proteins in a dose-dependent manner. Notably, the decreased UQCRC2 and TYP were associated with reduced sperm kinematics, ATP production, and capacitation, which ultimately led to adverse effects on male fertility such as poor fertilization rates and embryo development. Thus, nutlin-3a may be considered as a potential male contraceptive agent due to its ability to decrease fertility secondary to changes in overall sperm physiology and embryonic development. However, the results of this preliminary study have to be confirmed by additional independent trial.
Highlights
Normal spermatozoa are essential for successful fertilization of the female gamete both in vitro and in vivo, as well as for normal embryonic development
Results show an important role for nutlin-3a in sperm function via regulation of Ubiquinol-cytochrome-c reductase core protein 2 (UQCRC2), tyrosine phosphorylation (TYP) as well as associated changes of p53 ubiquitination
We found that nutlin-3a effectively decreased sperm motion kinematics, capacitation, and the acrosome reaction in a dose-dependent manner, with significant negative effects at the highest concentration tested (100 μM)
Summary
Normal spermatozoa are essential for successful fertilization of the female gamete both in vitro and in vivo, as well as for normal embryonic development. These processes require that the spermatozoa possess a specific set of proteins. Protein ubiquitination alters protein activity and induces proteolysis via the 26S proteasome [1]. P53, a protein associated with ubiquitination, is an essential protein present during spermatogenesis that causes DNA damage and eliminates spermatogenic cells. TheMDM2 repressor can potentially bind the N-terminus of p53, and in turn promote ubiquitination which allows the protein to move from the nucleus to the cytoplasm of the cell, where p53 can be degraded by cytoplasmic proteasomes [2]. It was reported that expression of ubiquinol-cytochrome c reductase core protein II (UQCRC2) in spermatozoa was correlated with male fertility [4]
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