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Role of Glycolysis and Respiration in Sperm Metabolism and Motility

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Role of Glycolysis and Respiration in Sperm Metabolism and Motility ROLE OF GLYCOLYSIS AND RESPIRATION IN SPERM METABOLISM AND MOTILITY A thesis submitted to Kent State University in partial fulfillment of the requirements for the degree of Master of Science By Vinay Pasupuleti December, 2007 Thesis written by Vinay Pasupuleti M.B., B.S., Kasturba Medical College, 2001 M.S., Kent State University, 2007 Approved by ______________________________, Advisor S. Vijayaraghavan ______________________________, Director, School of Biomedical Sciences Robert V. Dorman ______________________________, Dean, College of Arts and Sciences Jerry Feezel ii TABLE OF CONTENTS ACKNOWLEDGEMENTS …………………………………………….…………….v INTRODUCTION ……………………………………………………………….……1 Background ………………………………………………………………........1 Aims ………….….……………………………………………………...……13 METHODS ………………………………………………………….……………….14 RESULTS ………………………………………………………………….………...19 DISCUSSION ………………………………………………………….……….……38 REFERENCES……………………...………………………………….…………….47 iii LIST OF FIGURES Figure 1. Anatomy of spermatozoa………………….……….…………………….….3 Figure 2. Glycolysis …………………………………………………….….……...…..7 Figure 3. ATP production from glycolysis and respiration……………………………8 Figure 4. Sperm ATP and motility in media sustaining glycolysis or respiration ...…20 Figure 5. Effect of DOG on sperm ATP and motility in presence of pyruvate and lactate………………………………………………………………………22 Figure 6. Effect of iodoacetamide on sperm ATP and motility in presence of pyruvate and lactate………………………………………………………...........23, 24 Figure 7. Effect of DOG and iodoacetamide on sperm ATP and motility in presence of glucose……………………………………………...…………………...25 Figure 8. Effect of DOG on sperm ATP and motility in presence of fructose…….....27 Figure 9. Western blot of mouse sperm extracts probed with GSK-3α antibody.........28 Figure 10. Aligned GSK-3α peptide sequence of human, rat and mouse……...…...…30 Figure 11. Western blot of mouse sperm extracts probed with GSK-3α/β antibody.....31 Figure 12. Western blot of bovine sperm extracts probed with GSK-3α antibody…...32 Figure 13. Intracellular localization of GSK-3α/β in mouse sperm ………….…….…34 Figure 14. Intracellular localization of GSK-3α/β in bovine sperm …………….…….35 Figure 15. Sperm ATP and motility in presence of GSK-3 inhibitors…………..…….37 Figure 16. Schematic of modes of action of DOG and iodoacetamide…………….….46 iv ACKNOWLEDGEMENTS The author extends his sincere gratitude to the following individuals: Dr. Srinivasan Vijayaraghavan, Department of Biological Sciences, Kent State University for his guidance and support throughout the duration of this endeavor. Dr. Douglas Kline and Dr. Jennifer L. Marcinkiewicz, my committee members, for their valuable time and advice. Pawan Puri, doctoral student in Department of Biological Sciences and Dr. Rumela Chakrabarti, for their help with the experiments and review of the thesis. v INTRODUCTION Background Motility is a characteristic function of most male gametes and this feature enables the spermatozoa to reach a female gamete for fertilization. The sperm must be highly motile for an extended period of time under varying conditions. Despite decades of research, relatively little is known about how various metabolic and biochemical pathways operate to induce and sustain motility in mature spermatozoa. Several intracellular mediators and exogenous substances have been found to stimulate or inhibit motility in spermatozoa. A complete understanding of energy utilization and the mechanism of motility mediators will ultimately lead to the elucidation of this complex biological process. Spermatogenesis Spermatogenesis is the process by which a complex, interdependent population of germ cells produces spermatozoa. Three major stages can be distinguished: spermatogoniogenesis, meiosis of spermatocytes and spermiogenesis. Spermatogenesis occurs within the seminiferous tubules of the testes in intimate association with Sertoli cells. Sertoli cells provide nourishment and protection to the developing gametes. Leydig cells in the interstitial spaces between the tubules secrete testosterone hormone which is essential to spermatogenesis. During spermatogoniogenesis, germ cells divide 1 2 mitotically to form spermatogonia, some of which differentiate and undergo mitotic division to form primary spermatocytes. The meiotic division of primary spermatocytes produces secondary spermatocytes which complete the second meiotic division to form spermatids. Spermatids are haploid, round, cells without flagella that differentiate morphologically to form mature spermatozoa by a process called spermiogenesis. During spermiogenesis, spermatids begin to grow a tail, and develop a thickened mid-piece, where the mitochondria gather around an axoneme. The chromatin undergoes packaging, becoming highly condensed and transcriptionally inactive. The Golgi apparatus surrounds the condensed nucleus, becoming the acrosome. Mature spermatozoa are released into the seminiferous tubule lumen at the completion of spermiogenesis. A complete spermatogenetic cycle from spermatogonium to mature spermatozoa requires approximately 56 days in a mouse and 65 days in humans. Spermatozoa The two main components of the mature sperm are the head and flagellum, as shown in Fig.1. The head contains the nucleus, acrosome and a small amount of cytoplasm. The flagellum is divided successively into midpiece, principal piece and the end piece. It contains the central complex of microtubules forming the axoneme, surrounded in turn by outer dense fibers extending from the neck into the principal piece. The midpiece contains the mitochondria. The axoneme has the conserved “9+2” structure, consisting of a central doublet of microtubules surrounded by a ring of nine A/B microtubule doublets [1]. 3 Fig.1. Anatomy of a bovine spermatozoon. A mature spermatozoa consists of a head containing the acrosome and the nucleus, the mid-piece containing the mitochondria, the tail and the end-piece. Spermatozoon maturation Sperm morphogenesis is accomplished in the testis, but testicular sperm remain physiologically “immature”. Once formed within the seminiferous tubules, the immotile spermatozoa are released into luminal fluid and transported into epididymis, where they gain the ability to move [2]. Epididymal maturation of spermatozoa is an androgen dependent process [3]. The testicular spermatozoa are transported passively into the rete 4 testis and then to the epididymis via the efferent ducts. The efferent ducts absorb most of the fluid discharged from the testis with the spermatozoa, thus increasing the epididymal sperm concentration [4]. The epididymis can be divided into three parts: caput, corpus and cauda. In most mammals, the transit of spermatozoa through the epididymis usually takes 10-13 days and in humans the estimated transit time is 2-6 days [5]. Generally, spermatozoa isolated from the caput epididymis are immotile and spermatozoa isolated from the caudal epididymis show high motility and forward progression [6-8]. To attain the capacity to fertilize, sperm undergo many maturational changes during its transit in the epididymal duct [4]. These include changes in plasma membrane lipids, proteins and glycosylation, alterations in the outer acrosomal membrane and cross-linking of nuclear protamines and proteins of the outer dense fiber and fibrous sheath. Spermatozoa are maintained in a low energy consumption state during epididymal storage in the cauda epididymis, thus conserving energy and favoring long-term survival of the cells [9]. Motility is activated when spermatozoa contact substances in semen upon ejaculation [10]. Sperm artificially isolated from the caput and caudal epididymis are called caput sperm and caudal sperm respectively and are used to study changes in motility parameters and metabolism. Though caudal spermatozoa are motile they are unable to fertilize the egg. Spermatozoa need to undergo further maturational changes including capacitaion, hyperactivation and acrosome reaction before they can fuse with the female gamete. These changes begin once sperm are deposited into the female reproductive tract. Capacitation is initiated and possibly already completed in the cervix [11]. During 5 capacitation there are changes in the sperm plasma membrane, intracellular ions, metabolism, nucleus and acrosome [12]. Hyperactivation takes place in the oviduct and helps the spermatozoa to swim in the viscous oviduct fluid [13]. The acrosome reaction enables spermatozoa to penetrate through the zona pellucida and fuse with the egg plasma membrane [14]. Mechanics of flagellar motility Activation of sperm flagellar motility involves activation of both energy metabolism and the motile apparatus. The flagellar movement is generated by the motor activities of the axonemal dynein arms working against stable microtubule doublets. The initiation of the flagellar waveform is dependent on the phosphorylation of the axonemal dynein [15]. After phosphorylation, the dynein ATPase is activated. The energy released by the hydrolysis of ATP, converted to force, causes the microtubules to slide past one another [16, 17]. Dephosphorylation of dynein by the calmodulin-dependent protein phosphatase calcineurin then reverses the process [18]. The phosphorylation/dephosphorylation and the corresponding activation and inactivation of the dynein arms occur in an asynchronous manner around the circumference and along the length of the axoneme [19]. The axoneme propagates bends in both directions by regulating the timing and location in which dynein arms are active [1]. The sliding activity of the
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