Clinical Implications Mitochondrial ROS and DNA Damage

A strong marker for oxidative DNA damage is the major oxidized base adduct formed when DNA is subjected to attack by ROS, 8OHdG. Clinically, this marker has been shown to be higher in spermatozoa of subfertile patients [132]. The importance and clinical implications of oxidative DNA damage will be covered in Chap. 11, although it is important to further emphasize the ability of mitochondrial ROS to contribute to nuclear DNA damage. Admittedly mtDNA damage is a common factor and contributor of excessive ROS generation; it is also critical to note that paternal mtDNA is not passed onto the offspring during fertilization and development. However, despite the physical barriers that separate the sperm head from the midpiece, mitochondrial ROS has been shown to be capable of inducing oxidative damage to nuclear in a number of recent studies via different stimuli including activation of apoptosis though inhibition of PI3-kinase inhibitor, wortmannin [99], or through direct stimulation of mitochondrial ROS through exposing spermatozoa to PUFAs or EMR [53, 87]. Importance in IVF and Targeted Antioxidant Therapy

Clinically, the importance of oxidative stress-mediated male infertility has given rise to the trial of antioxidant therapies. While a number of research studies have focused on a single antioxidant's effects, current commercial treatments such as MenevitĀ© use a broad range of antioxidant compounds in order to address oxidative stress-related male infertility. In light of evidence presented in this chapter, it may prove beneficial to develop antioxidant trials and therapies that specifically target mitochondria. From this perspective, the most logical candidate is coenzyme Q10 (CoQ10), a well-known mitochondrial antioxidant component.

Although CoQ10 has a number of physiological roles including redox carrier, activator of uncoupling proteins, and in mitochondrial pore formation [133], CoQ10 in its reduced form (CoQH2) is a powerful antioxidant through its ability to inhibit destructive lipid peroxidation chains. The effectiveness of CoQH2 as an inhibitor of lipid peroxidation is through its ability to break the complex chain reactions produced during lipid peroxidation cascades. In this process, CoQ10 prevents the formation of lipid peroxyl radicals (LOOt production during initiation phase of lipid peroxidation. The reduced form of CoQ10 reduces the initiating peroxyl radical via the formation of a semiquinone and H2O2. Alternatively, CoQH2 can eliminate LOOt directly. This is achieved again via the formation of a semiquinone, the same mechanism by which a-tocopherol prevents lipid peroxidation [134].

There are a number of pathologies where oxidative stress is a well-documented contributing factor that also exhibits increases in the synthesis of CoQ10 including Alzheimer's, prion, other neurodegenerative disease, and diabetes [135]. During both aging and in heart disease, there is a significant lowering of CoQ10 content in the target organ [136], creating a state of vulnerability to oxidative stress. Since mitochondrial ROS generation is a continual and unavoidable by-product of cellular respiration, conditions associated with a decreased availability of CoQ10 in the male reproductive tract may well be associated with oxidative stress. Given the preliminary evidence for CoQ10 as a major antioxidant in the male reproductive tract [137-139L further studies should be undertaken to examine the potential inclusion of this coenzyme as a candidate for the antioxidant therapy of male infertility such as the in vivo study by Balercia et al. [140] that showed increased sperm motility in infertile men with asthenozoospermia treated with CoQ10 for 6 months.

However, while it is an effective and a viable option for those undergoing ART, antioxidant therapy is an approach that only addresses the symptoms of this condition; it does not address the underlying causative mechanisms.

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