New insights into male (in)fertility: the importance of NO

Abstract

Infertility is a global problem that is on the rise, especially during the last decade. Currently, infertility affects approximately 10-15% of the population worldwide. The frequency and origin of different forms of infertility varies. It has been shown that reactive oxygen and nitrogen species (ROS and RNS) are involved in the aetiology of infertility, especially male infertility. Various strategies have been designed to remove or decrease the production of ROS and RNS in spermatozoa, in particular during in vitro fertilization. However, in recent years it has been shown that spermatozoa naturally produce a variety of ROS/RNS, including superoxide anion radical (O2 (⋅-)), hydrogen peroxide and NO. These reactive species, in particular NO, are essential in regulating sperm capacitation and the acrosome reaction, two processes that need to be acquired by sperm in order to achieve fertilization potential. In addition, it has recently been shown that mitochondrial function is positively correlated with human sperm fertilization potential and quality and that NO and NO precursors increase sperm motility by increasing energy production in mitochondria. We will review the new link between sperm NO-driven redox regulation and infertility herein. A special emphasis will be placed on the potential implementation of new redox-active substances that modulate the content of NO in spermatozoa to increase fertility and promote conception.

Figure 1

NO regulates sperm functions. At physiological levels, NO and RNS regulate essential sperm-fertilizing events. At supra-physiological levels NO achieves detrimental effects on above shown sperm function. PLCγ1, phosphoinositide-specific phospholipase γ1.

Figure 2

Importance of mitochondria in regulation of sperm functions. Mitochondria supply spermatozoa with energy (ATP) for vital sperm-fertilizing processes. In addition, through production of ROS and RNS and subsequent activation of various redox-dependent signalling pathways, mitochondria are involved in the regulation of sperm functions. Other roles of mitochondria in spermatozoa, such as Ca²⁺ signalling and protein synthesis, have also been presented.

Figure 3

Structure of M40403, a SOD mimic.

Figure 4

Strategies to modify NO concentration in spermatozoa. As a substrate for NOSs, l-arginine increases NO production. In contrast, the SOD mimic removes O₂^⋅−, and by decreasing the bioavailability of O²⁻ for interaction with NO, the amount of NO consequently increases.