Abstract
Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells.
Highlights
Fertility and Oxidative StressA decline in fertility rates is becoming an increasingly prevalent issue worldwide, with current estimates indicating that 1 in every 6 couples experience issues with conception [1].the contribution of male factor infertility accounts for up to half of these cases [2].The leading cause of male infertility stems from a loss of sperm function, resulting in a loss of fertilization potential [3]
reactive oxygen species (ROS) actively participate in metabolic pathways during sperm activation, which leads to cholesterol efflux, cyclic adenosine monophosphate production and tyrosine phosphorylation, important events that contribute to fertilization competence [5,7,8,9]
This study proposes that an overexpression of ALOX15 stimulates the production of pro-inflammatory mediators, which promote insulin resistance induced through a high fat diet [72]
Summary
A decline in fertility rates is becoming an increasingly prevalent issue worldwide, with current estimates indicating that 1 in every 6 couples experience issues with conception [1]. Spermiogenesis, a process that gives rise to the unique architecture intracellular ROS production escalates beyond the buffering antioxidant capacity of the cell in a state of mature spermatozoa, results in significant cytoplasmic depletion [14,15], thereby diminishing of oxidative stress, the redox biochemistry leads to damaging effects such as lipid peroxidation, antioxidant capacity in the DNA spermatozoon. This facilitates electron leakage to electron acceptors in an unregulated fashion, increasing the production of ROS and eventually precipitating a state of oxidative stress within the cell [19] Another such example in human spermatozoa is the molecular chaperone HSPA2 [34], which is targeted for adduction by 4HNE [25]. We investigate in more detail the involvement of lipoxygenase proteins in the enzymatic production of 4HNE
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