Intrinsic Causes of Mitochondrial ROS Generation

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There is evidence for the role of mitochondrial ROS in the etiology of male infertility in human spermatozoa. Although the factors responsible for stimulating increased free radical release from the mitochondria of spermatozoa are still unresolved, recent research suggests the involvement for a number of intrinsic factors including FAs and apoptosis. Fatty Acids

The fatty acid (FA) composition within spermatozoa plays a crucial role in the ability of these cells to achieve fertilization. The high unsaturated FA content within the sperm plasma membrane is critical for function, although also results in increased susceptibility as targets for lipid peroxidation. Greater detail on this topic will be covered in Chap. 6.

A number of studies have described differing influences of FAs on mitochondrial function. Research by Cocco et al. [85] showed that the addition of endogenous fatty acids to isolated bovine heart mitochondria caused 81% and 32% inhibition of the ETC complexes I and III, respectively. The inhibition of mitochondrial ETC complexes was specific to only unsaturated fatty acids, as saturated fatty acids did not elicit an effect [85]. Interestingly, in line with these results, inhibition of complex I, not complex III, in human spermatozoa results in peroxidative damage and reduction in fertility potential [27].

It has been previously indicated by Aitken et al. [86] that addition of polyun-satutared fatty acids (PUFAs) to human spermatozoa results in increased ROS generation, lipid peroxidation, and motility loss. However, at the time the source of the ROS was not determined, although lipoxygenase and cycloxygenase pathways were excluded as mediators of this response. Subsequent data have now been shown by Koppers et al. [87], recognizing that the mitochondria are the source of ROS and damaging oxidative stress following addition of endogenous PUFA. The addition of any unsaturated FA analyzed in the study (omega-3, -6, -9) to human spermatozoa results in increased mitochondrial ROS generation, albeit at differing levels. The oxidative stress created by FA-stimulated mitochondria resulted in a significant decrease in sperm motility and the associated induction of oxidative DNA damage. The same study demonstrated that dysfunctional human spermatozoa, separated via density gradient centrifugation, contain significantly more FA than their functional counterparts. This FA excess applied to all classes of FA (saturated, monounsaturated, and polyunsaturated) and was also observed regardless of whether analyzed as the total FA content of these cells or only the unesterified (free) FA component. This confirms an earlier study by Ollero et al.

[88], who observed an increase in the PUFA (particularly DHA) content of defective spermatozoa.

Koppers et al. [87] were the first to reveal that highly significant correlations exist between spontaneous mitochondrial ROS production by human spermatozoa and their free (unesterified) unsaturated FA content for both omega-6 (R2=0.605) and omega-3 (R2 = 0.615) PUFAs. The findings are also consistent with previous analysis of the FA content of human spermatozoa, which observed an increase in the cellular content of both saturated and unsaturated FAs in spermatozoa from men seeking infertility treatment compared to a cohort of normozoospermic controls

[89]. Overall these results have established a causal link between the levels of unsaturated FAs in human spermatozoa, mitochondrial ROS generation, and its adverse effect on function.

Recent evidence suggests that systemic deficiencies in lipid metabolism seem an unlikely cause of increased FA content in spermatozoa given the apparent discrepancy between the FA profiles of blood serum and spermatozoa [90], Alternatively, the high FA content of defective spermatozoa likely reflects a fundamental error in the remodeling of human sperm cells during spermiogenesis, which would be associated with the increased retention of residual cytoplasm and an enhanced cytoplasmic volume. Apoptosis

Apoptosis due to oxidative stress is usually only observed in pathological conditions [91, 92]. Increased mitochondrial ROS is one known trigger of the intrinsic apop-totic pathway, which is achieved via an increase in the permeability of the outer mitochondrial membrane through the opening of transition pores. The opening of the permeability transition pore is favored by oxidative stress through oxidation of intracellular GSH and other critical sulfhydryl groups [93]. Under normal conditions, various antiapoptotic factors (including Bcl-xL) prevent increases in mito-chondrial permeability as long as they remain bound to the outer membrane; the translocation of Bax to the mitochondria removes these antiapoptotic factors initiating apoptosis [ 94] . The opening of permeability transition pores results in the gradual loss of cytochrome c from the intermembrane space during apoptosis. As cytochrome c is released, the respiratory chain becomes more reduced as electron flow between complexes III and IV slows down resulting in increased semiquinone formation and thus ROS [95].

Mature human spermatozoa have been recognized to exhibit many but not all features of apoptotic signal transduction pathways including the externalization of phosphatidylserine (PS) (annexin-V binding), activation of caspases 1, 3, 8, and 9 [96-98], mitochondrial dysfunction, and ROS generation [99-101]. One pathology that has been associated with apoptosis in spermatozoa is varicocele. Spermatozoa from men with this condition show higher levels of externalization of PS mitochondrial dysfunction and nuclear DNA damage [102]. In vitro exposure of human spermatozoa to oxidative stress mediator H2O2 can trigger the activation of caspases and externalization of PS [103]. In contrast, addition of antioxidants (catalase) to spermatozoa prior to H2 O2 will prevent this apoptotic response [104]. Activation of the apoptotic cascade by PI3 kinase inhibitor, wort-mannin, has also shown to result in increased mitochondrial ROS generation, caspase activation, and PS externalization [99],

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Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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