Male infertility is a distressingly common condition affecting at least 1 in 20 men. In recent years, oxidative stress has been shown to be exceedingly common in the infertile male cohort. We have observed that reactive oxygen species plays a key role in sperm dysfunction and indeed products of oxidative stress, nucleophilic aldehydes, may adduct and disrupt the molecular chaperone HSPA2. This protein is responsible for facilitating the expression of an oocyte-receptor complex to the sperm surface, essential for processes leading to fertilisation. Recent data has implicated two client proteins, SPAM1 and ARSA that form a zona pellucida–receptor complex regulated by the molecular chaperone HSPA2. We have used a combination of molecular, mass spectroscopy and molecular modelling approaches to study the structure of the oocyte-receptor complex and further, to identify the molecular mechanisms arising from oxidative stress that lead to disruption of complex formation and therefore failure to bind to the oocyte.
Our preliminary data has revealed that under a state of oxidative stress, HSPA2 becomes alkylated by reactive aldehydes, specifically 4-hydroxynonenal (4HNE). We have also identified adduct formation at Cys267, an amino acid that is critical for the chaperoning activity of HPSA2. This is consistent with the demonstration that 4HNE adduction disrupts HSPA2-client protein interactions (assessed by blue native), leading to dissociation of HSPA2 complexes. We are now focused on detailing the molecular nature of HSPA2 modifications driven by oxidative stress. We also aim to understand the structural impact of this damage and how it specifically influences the ability of HSPA2 to orchestrate oocyte-receptor complex assembly.
As oxidative stress is an emerging aetiology for male infertility, understanding the fundamental mechanisms behind the loss of sperm-oocyte binding, provides a strong platform for the rational design of targeted antioxidant therapies, tailored to this specific class of male infertility.