Nutlin-3a decreases male fertility via UQCRC2

PLoS One. 2013 Oct 9;8(10):e76959. doi: 10.1371/journal.pone.0076959. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Electron Transport Complex III / metabolism*
  • Embryonic Development / drug effects
  • Fertility / drug effects*
  • Imidazoles / pharmacology*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Reproduction / drug effects
  • Sperm Motility / drug effects
  • Spermatozoa / drug effects
  • Spermatozoa / physiology
  • Tyrosine / metabolism

Substances

  • Imidazoles
  • Piperazines
  • UQCRC2 protein, mouse
  • Tyrosine
  • nutlin 3
  • Adenosine Triphosphate
  • Electron Transport Complex III
  • Calcium

Grant support

This research was supported by the Rural Development Administration, Republic of Korea, through a project entitled the “Cooperative Research Program for Agriculture Science & Technology Development” (Project No. PJ008415), which is currently being implemented in the Department of Animal Science and Technology, Chung-Ang University, Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.