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Review
. 2020 Feb 4;9(2):134.
doi: 10.3390/antiox9020134.

Molecular Changes Induced by Oxidative Stress That Impair Human Sperm Motility

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Free PMC article
Review

Molecular Changes Induced by Oxidative Stress That Impair Human Sperm Motility

Karolina Nowicka-Bauer et al. Antioxidants (Basel). .
Free PMC article

Abstract

A state of oxidative stress (OS) and the presence of reactive oxygen species (ROS) in the male reproductive tract are strongly correlated with infertility. While physiological levels of ROS are necessary for normal sperm functioning, elevated ROS production can overwhelm the cell's limited antioxidant defenses leading to dysfunction and loss of fertilizing potential. Among the deleterious pleiotropic impacts arising from OS, sperm motility appears to be particularly vulnerable. Here, we present a mechanistic account for how OS contributes to altered sperm motility profiles. In our model, it is suggested that the abundant polyunsaturated fatty acids (PUFAs) residing in the sperm membrane serve to sensitize the male germ cell to ROS attack by virtue of their ability to act as substrates for lipid peroxidation (LPO) cascades. Upon initiation, LPO leads to dramatic remodeling of the composition and biophysical properties of sperm membranes and, in the case of the mitochondria, this manifests in a dissipation of membrane potential, electron leakage, increased ROS production and reduced capacity for energy production. This situation is exacerbated by the production of cytotoxic LPO byproducts such as 4-hydroxynonenal, which dysregulate molecules associated with sperm bioenergetic pathways as well as the structural and signaling components of the motility apparatus. The impact of ROS also extends to lesions in the paternal genome, as is commonly seen in the defective spermatozoa of asthenozoospermic males. Concluding, the presence of OS in the male reproductive tract is strongly and positively correlated with reduced sperm motility and fertilizing potential, thus providing a rational target for the development of new therapeutic interventions.

Keywords: 4-hydroxynonenal (4HNE), infertility; lipid peroxidation; male germ cells; oxidative stress; reactive oxygen species; sperm capacitation; sperm motility; spermatozoa.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Sources of reactive oxygen species (ROS) in human spermatozoa and the relationship between the rate of their production and antioxidant defenses during oxidative stress. (b) ROS are capable of attacking polyunsaturated fatty acids (PUFAs) within cellular membranes, initiating lipid peroxidation cascades (LPO) and resulting in the production of cytotoxic lipid aldehydes such as 4-hydroxynonenal (4HNE). Abbreviations: EME, electromagnetic energy; ETC, electron transport chain.
Figure 2
Figure 2
The influence of 4-hydroxynonenol (4HNE) on sperm function. The lipid aldehyde 4HNE has repeatedly been shown to form adducts with sperm flagellum proteins associated with the motility apparatus, signaling pathways and metabolism. In the context of the mitochondria, 4HNE adduction has been linked to adverse effects on enzymes of beta-oxidation, the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC), thus attenuating the energy production. Abbreviations: CI, ETC Complex I; CII, ETC Complex II; CIII, ETC Complex III; CIV, ETC Complex IV; DA, dynein arms; FS, fibrous sheath; MT, microtubules; ODF, outer dense fibers.
Figure 3
Figure 3
Mitochondrial DNA and location of the mtDNA 4977 bp and 7436 bp deletions. The mtDNA4977 deletion includes genes encoding two subunits of ATP-synthase (ATP6 and ATP8), cytochrome oxidase III (COIII), NADH dehydrogenase subunit 3 (ND3), ND4, ND4 subunit L (ND4L), and ND5, whereas mtDNA7436 includes ATP6, COIII, ND3, ND4, ND4L, ND5, ND6 and the entire cytochrome b (Cyt b). As a consequence, spermatozoa harboring mtDNA4977 and mtDNA7436 deletions lack several essential OXPHOS genes, fail to assemble functional ETC complexes, and experience compromised energy production. Abbreviations: CI, ETC Complex I; CIII, ETC Complex III; CIV, ETC Complex IV.

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