ROS, Thiols and Thiol-Regulating Systems in Male Gametogenesis☆
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BBAGEN-28068; No. of pages: 9; 4C: 6, 7 Biochimica et Biophysica Acta xxx (2014) xxx–xxx Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen Review ROS, thiols and thiol-regulating systems in male gametogenesis☆ Marcus Conrad a,⁎, Irina Ingold a, Katalin Buday a, Sho Kobayashi a,b, Jose Pedro Friedmann Angeli a a Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany b Department of Functional Genomics and Biotechnology, United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate 020-8550,Japan article info abstract Article history: Background: During maturation and storage, spermatozoa generate substantial amounts of reactive oxygen Received 9 September 2014 species (ROS) and are thus forced to cope with an increasingly oxidative environment that is both needed and Received in revised form 17 October 2014 detrimental to their biology. Such a janus-faceted intermediate needs to be tightly controlled and this is done Accepted 20 October 2014 by a wide array of redox enzymes. These enzymes not only have to prevent unspecificmodifications of essential Available online xxxx cellular biomolecules by quenching undesired ROS, but they are also required and often directly involved in critical protein modifications. Keywords: Scope of review: The present review is conceived to present an update on what is known about critical roles of Glutathione peroxidase Oxidative stress redox enzymes, whereby special emphasis is put on the family of glutathione peroxidases, which for the time Selenoproteins being presents the best characterized tasks during gametogenesis. Selenium Major conclusions: We therefore demonstrate that understanding the function of (seleno)thiol-based oxidases/ Spermatogenesis reductases is not a trivial task and relevant knowledge will be mainly gained by using robust systems, as exemplified by several (conditional) knockout studies. We thus stress the importance of using such models for providing unequivocal evidence in the molecular understanding of redox regulatory mechanisms in sperm maturation. General significance: ROS are not merely detrimental by-products of metabolism and their proper generation and usage by specific enzymes is essential for vital functions as beautifully exemplified during male gametogenesis. As such, lessons learnt from thiol-based oxidases/reductases in male gametogenesis could be used as a general principle for other organs as it is most likely not only restricted to this developmental phase. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. © 2014 Elsevier B.V. All rights reserved. 1. Introduction changes [1], the haploid spermatids undergo dramatic morphological alterations and elongate. These changes include the formation of the tail Sperm development is a complex process involving a series of highly (from a centriole), of the axoneme (by microtubules) and of the acrosome orchestrated steps including stem cell proliferation and renewal, genetic (from the Golgi apparatus), replacement of the majority of histones by remodeling including genetic exchange between sister chromatids and transition proteins and finally by protamines leading to tight packaging properly controlled reduction of chromosomes, dramatic morphological of the male haploid genome, and removal of unnecessary cytoplasm alterations and eventually sperm activation, a process known as and organelles, leading to the formation of the so-called residual bodies. capacitation. During spermatogenesis, the diploid spermatogonial In a process called spermiation, elongated spermatozoa are eventually stem cells that originally derive from gonocytes either go through released into the lumen of the seminiferous tubule. The still immobile self-renewal proliferation in order to maintain the population of spermatozoa are then transported to the epididymis where they acquire stem cells or differentiate into primary spermatocytes. These diploid motility and the capability to fertilize in addition to a further oxidation spermatocytes undergo the first round out of meiotic division resulting in of sperm proteins as summarized below. Aberrant control of any these two haploid secondary spermatocytes, which upon the second meiotic steps frequently contributes to male infertility, testicular cancer, germ division yield two haploid spermatids (spermatidogenesis). In a subse- cell mutations, miscarriages and progenies with disabilities. Although quent developmental process, known as spermiogenesis that can be many of the steps involved in proper male gametogenesis are known further subdivided into 16 stages in mice according to morphological and have been described in detail, a comprehensive knowledge about the role of ROS and systems generating partly reduced forms of oxygen and those keeping them at physiological concentrations is still scant. ☆ This article is part of a Special Issue entitled Redox regulation of differentiation fi and de-differentiation. This is particularly astonishing in light of the very early and actually rst ⁎ Corresponding author. Tel.: +49 89 3187 4608; fax: +49 89 3187 4288. observation in mammals that it is the spermatozoon that deliberately E-mail address: [email protected] (M. Conrad). produces ROS [2]. This lack of knowledge is mainly due to inherent http://dx.doi.org/10.1016/j.bbagen.2014.10.020 0304-4165/© 2014 Elsevier B.V. All rights reserved. Please cite this article as: M. Conrad, et al., ROS, thiols and thiol-regulating systems in male gametogenesis, Biochim. Biophys. Acta (2014), http:// dx.doi.org/10.1016/j.bbagen.2014.10.020 2 M. Conrad et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx limitations to studying sperm development in vitro, the frequently Mitochondrial respiratory activity is essential for the rapid observed stark discrepancies between highly divergent redox conditions movement of released sperm for the fertilization process [11],and in vitro and in vivo and still insufficient genetic animals models to mitochondria are still being considered as a major site of ROS production unequivocally assign distinct redox-dependent processes to the individu- in sperm cells. Yet one needs to consider that mitochondrial respiration al steps of spermatogenesis in vivo. really picks up only in caudal sperm as glycolysis is not only an important Yet, a better knowledge about the molecular role of reactive oxygen process for delivering the sperm's energy demand at earlier stages species (ROS) and their surveillance systems in this vital process of sperm development [12,13], but also during its rapid movement [14, may not only guide us to predict and prevent diseases linked to 15]. Notwithstanding, mitochondrial inhibitors have been shown to ROS-induced aberrant spermatogenesis, but also might prove highly impair sperm motility, and thus fertilizing capacity; and incomplete useful in the further improvement of assisted fertility techniques, electron transfer and electron leakage mainly at complexes I and III are which is of particular relevance in a steadily decreasing proportion of known to ultimately lead to the generation of substantial amounts of fertile men in the Western world. Hence, it is the goal of this review ROS and thus oxidative stress, a major cause of defective sperm function to critically portray the role of ROS and ROS-regulating systems during and male infertility [16,17]. For instance, challenging human sperm with sperm development with special focus on the utilization of transgenic respiratory chain inhibitors specific for the individual complexes mouse models that has provided intriguing and often conclusive revealed that ROS generated at complex I had the most significant insights. adverse impact such as peroxidative damage of sperm midpiece and a loss of sperm movement [16]. Notably, these effects could be prevented 2. Reactive oxygen species: the source and nature of generation by the lipophilic antioxidant α-tocopherol. The latter is in line with the high abundance of poly unsaturated fatty acids (PUFAs) in sperm that ROS is an “umbrella” term and describes partly forms of molecular can be easily modified by oxidation leading to peroxidative breakdown oxygen that in part show high reactivity towards cellular components, of lipid bilayers [18], and the induction of subsequent apoptotic or including DNA, proteins and lipids. Some highly relevant forms of ROS non-apoptotic cell death paradigms. In this context, the naturally − in biological systems include singlet oxygen, superoxide anion (O2. ), occurring electrophilic lipid peroxidation breakdown 4-hydroxynonenal hydrogen peroxide (H2O2), hydroxyl radical (OH•), lipid hydroperoxide (4-HNE) and acrolein were recently reported to target succinate dehydro- (LOOH), phospholipid hydroperoxide (PLOOH) among others. ROS are genase in isolated human spermatozoa, leading to an increased ROS produced at virtually all subcellular compartments where they perform production and a concomitant decrease in sperm motility both of specific functions. Relevant sites of ROS generation include mitochondria, which could be compensated for by treatment of aldehyde-exposed endoplasmic reticulum (ER), cytosol, lysosomes, peroxisomes and at the spermatozoa with thiol containing nucleophiles [19,20]. plasma membrane [3]. Besides a number of environmental exposure Although lipid-associated peroxides