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Are sperm capacitation and apoptosis the opposite ends of a continuum driven by oxidative stress?

Aitken RJ, Baker MA, Nixon B - Asian J. Androl. (2015 Jul-Aug)

Bottom Line: As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization.These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa.A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre in Reproductive Science, Discipline of Biological Sciences and Hunter Medical Research Institute, University of Newcastle, NSW 2308, Australia.

ABSTRACT
This chapter explores the possibility that capacitation and apoptosis are linked processes joined by their common dependence on the continued generation of reactive oxygen species (ROS). According to this model capacitation is initiated in spematozoa following their release into the female reproductive tract as a consequence of intracellular ROS generation, which stimulates intracellular cAMP generation, inhibits tyrosine phosphatase activity and enhances the formation of oxysterols prior to their removal from the sperm surface by albumin. The continued generation of ROS by capacitating populations of spermatozoa eventually overwhelms the limited capacity of these cells to protect themselves from oxidative stress. As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization. The latter may be particularly important in instructing phagocytic leukocytes that the removal of senescent, moribund spermatozoa should be a silent process unaccompanied by the generation of proinflammatory cytokines. These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa. A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.

No MeSH data available.


Related in: MedlinePlus

Proposed pathways mediating the redox regulation of sperm capacitation and the initiation of apoptosis. (a) (1) In capacitating spermatozoa ROS generation is possibly elevated because of an increase in NADPH oxidase activity subsequent to activation of the hexose monophosphate shunt activity and the enhanced availability of NADPH.76 (2) The second source of O2-• in mammalian spermatozoa are the mitochondria in the sperm midpiece which generate a low level of ROS during steady state respiration. (3) The O2-• generated from these sources is thought to combine with NO produced as a consequence of nitric oxide synthase activity to generate the powerful oxidant, peroxynitrite (ONOO-), which mediates the oxidation of sterols that then exit the plasma membrane generating a dramatic increase in membrane fluidity as a consequence. (4) The combined action of ONOO- and H2O2 (generated as a result of superoxide dismutase activity), leads to the inhibition of tyrosine phosphatase activity, thereby facilitating tyrosine phosphorylation. (5) The combination of O2-•, HCO3- and Ca2+, activates soluble adenylyl cyclase stimulating cAMP production and the activation of PKA. The latter both directly activates SRC kinases (pp60cSRC and cABL) and simultaneously suppresses an inhibitor of SRC, C-terminal SRC kinase; as a result, SRC activity is significantly increased. (6) SRC then phosphorylates and inactivates a protein phosphatase permitting the dramatic upregulation of tyrosine phosphorylation that characterizes the capacitated state.77 (b) (7) When the oxidative stress associated with capacitation overwhelms the limited antioxidant defences offered by spermatozoa the cells enter the intrinsic apoptotic cascade, one of the early features of which is an increase in mitochondrial ROS. (8) Mitochondrial ROS generation induces the formation of small molecular mass aldehydes such as 4HNE which bind to the mitochondrial electron transport chain and stimulate yet more ROS generation in a self-perpetuating cascade. This further enhances the oxidative damage to the cell impairing motility and activating caspases. (9) During the advanced stages of apoptosis, phosphatidylserine appears on the exofacial surface of the spermatozoa and acts as a signal promoting the silent phagocytosis of these cells by dendritic cells, macrophages and neutrophils following insemination. ROS: reactive oxygen species; PKA: protein kinase A.
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Figure 1: Proposed pathways mediating the redox regulation of sperm capacitation and the initiation of apoptosis. (a) (1) In capacitating spermatozoa ROS generation is possibly elevated because of an increase in NADPH oxidase activity subsequent to activation of the hexose monophosphate shunt activity and the enhanced availability of NADPH.76 (2) The second source of O2-• in mammalian spermatozoa are the mitochondria in the sperm midpiece which generate a low level of ROS during steady state respiration. (3) The O2-• generated from these sources is thought to combine with NO produced as a consequence of nitric oxide synthase activity to generate the powerful oxidant, peroxynitrite (ONOO-), which mediates the oxidation of sterols that then exit the plasma membrane generating a dramatic increase in membrane fluidity as a consequence. (4) The combined action of ONOO- and H2O2 (generated as a result of superoxide dismutase activity), leads to the inhibition of tyrosine phosphatase activity, thereby facilitating tyrosine phosphorylation. (5) The combination of O2-•, HCO3- and Ca2+, activates soluble adenylyl cyclase stimulating cAMP production and the activation of PKA. The latter both directly activates SRC kinases (pp60cSRC and cABL) and simultaneously suppresses an inhibitor of SRC, C-terminal SRC kinase; as a result, SRC activity is significantly increased. (6) SRC then phosphorylates and inactivates a protein phosphatase permitting the dramatic upregulation of tyrosine phosphorylation that characterizes the capacitated state.77 (b) (7) When the oxidative stress associated with capacitation overwhelms the limited antioxidant defences offered by spermatozoa the cells enter the intrinsic apoptotic cascade, one of the early features of which is an increase in mitochondrial ROS. (8) Mitochondrial ROS generation induces the formation of small molecular mass aldehydes such as 4HNE which bind to the mitochondrial electron transport chain and stimulate yet more ROS generation in a self-perpetuating cascade. This further enhances the oxidative damage to the cell impairing motility and activating caspases. (9) During the advanced stages of apoptosis, phosphatidylserine appears on the exofacial surface of the spermatozoa and acts as a signal promoting the silent phagocytosis of these cells by dendritic cells, macrophages and neutrophils following insemination. ROS: reactive oxygen species; PKA: protein kinase A.

Mentions: As a consequence of their structure, the only product of apoptosis that can move from the sperm midpiece to the nucleus in the sperm head is the H2O2 generated following the dismutation of mitochondrial superoxide anion. This is why most DNA damage in spermatozoa is oxidatively induced and why the oxidative base adduct, 8-hydroxy-2’-deoxyguanosine (8OHdG) is such a powerful and effective biomarker of sperm quality (Figure 1).47


Are sperm capacitation and apoptosis the opposite ends of a continuum driven by oxidative stress?

Aitken RJ, Baker MA, Nixon B - Asian J. Androl. (2015 Jul-Aug)

Proposed pathways mediating the redox regulation of sperm capacitation and the initiation of apoptosis. (a) (1) In capacitating spermatozoa ROS generation is possibly elevated because of an increase in NADPH oxidase activity subsequent to activation of the hexose monophosphate shunt activity and the enhanced availability of NADPH.76 (2) The second source of O2-• in mammalian spermatozoa are the mitochondria in the sperm midpiece which generate a low level of ROS during steady state respiration. (3) The O2-• generated from these sources is thought to combine with NO produced as a consequence of nitric oxide synthase activity to generate the powerful oxidant, peroxynitrite (ONOO-), which mediates the oxidation of sterols that then exit the plasma membrane generating a dramatic increase in membrane fluidity as a consequence. (4) The combined action of ONOO- and H2O2 (generated as a result of superoxide dismutase activity), leads to the inhibition of tyrosine phosphatase activity, thereby facilitating tyrosine phosphorylation. (5) The combination of O2-•, HCO3- and Ca2+, activates soluble adenylyl cyclase stimulating cAMP production and the activation of PKA. The latter both directly activates SRC kinases (pp60cSRC and cABL) and simultaneously suppresses an inhibitor of SRC, C-terminal SRC kinase; as a result, SRC activity is significantly increased. (6) SRC then phosphorylates and inactivates a protein phosphatase permitting the dramatic upregulation of tyrosine phosphorylation that characterizes the capacitated state.77 (b) (7) When the oxidative stress associated with capacitation overwhelms the limited antioxidant defences offered by spermatozoa the cells enter the intrinsic apoptotic cascade, one of the early features of which is an increase in mitochondrial ROS. (8) Mitochondrial ROS generation induces the formation of small molecular mass aldehydes such as 4HNE which bind to the mitochondrial electron transport chain and stimulate yet more ROS generation in a self-perpetuating cascade. This further enhances the oxidative damage to the cell impairing motility and activating caspases. (9) During the advanced stages of apoptosis, phosphatidylserine appears on the exofacial surface of the spermatozoa and acts as a signal promoting the silent phagocytosis of these cells by dendritic cells, macrophages and neutrophils following insemination. ROS: reactive oxygen species; PKA: protein kinase A.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492056&req=5

Figure 1: Proposed pathways mediating the redox regulation of sperm capacitation and the initiation of apoptosis. (a) (1) In capacitating spermatozoa ROS generation is possibly elevated because of an increase in NADPH oxidase activity subsequent to activation of the hexose monophosphate shunt activity and the enhanced availability of NADPH.76 (2) The second source of O2-• in mammalian spermatozoa are the mitochondria in the sperm midpiece which generate a low level of ROS during steady state respiration. (3) The O2-• generated from these sources is thought to combine with NO produced as a consequence of nitric oxide synthase activity to generate the powerful oxidant, peroxynitrite (ONOO-), which mediates the oxidation of sterols that then exit the plasma membrane generating a dramatic increase in membrane fluidity as a consequence. (4) The combined action of ONOO- and H2O2 (generated as a result of superoxide dismutase activity), leads to the inhibition of tyrosine phosphatase activity, thereby facilitating tyrosine phosphorylation. (5) The combination of O2-•, HCO3- and Ca2+, activates soluble adenylyl cyclase stimulating cAMP production and the activation of PKA. The latter both directly activates SRC kinases (pp60cSRC and cABL) and simultaneously suppresses an inhibitor of SRC, C-terminal SRC kinase; as a result, SRC activity is significantly increased. (6) SRC then phosphorylates and inactivates a protein phosphatase permitting the dramatic upregulation of tyrosine phosphorylation that characterizes the capacitated state.77 (b) (7) When the oxidative stress associated with capacitation overwhelms the limited antioxidant defences offered by spermatozoa the cells enter the intrinsic apoptotic cascade, one of the early features of which is an increase in mitochondrial ROS. (8) Mitochondrial ROS generation induces the formation of small molecular mass aldehydes such as 4HNE which bind to the mitochondrial electron transport chain and stimulate yet more ROS generation in a self-perpetuating cascade. This further enhances the oxidative damage to the cell impairing motility and activating caspases. (9) During the advanced stages of apoptosis, phosphatidylserine appears on the exofacial surface of the spermatozoa and acts as a signal promoting the silent phagocytosis of these cells by dendritic cells, macrophages and neutrophils following insemination. ROS: reactive oxygen species; PKA: protein kinase A.
Mentions: As a consequence of their structure, the only product of apoptosis that can move from the sperm midpiece to the nucleus in the sperm head is the H2O2 generated following the dismutation of mitochondrial superoxide anion. This is why most DNA damage in spermatozoa is oxidatively induced and why the oxidative base adduct, 8-hydroxy-2’-deoxyguanosine (8OHdG) is such a powerful and effective biomarker of sperm quality (Figure 1).47

Bottom Line: As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization.These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa.A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.

View Article: PubMed Central - PubMed

Affiliation: Priority Research Centre in Reproductive Science, Discipline of Biological Sciences and Hunter Medical Research Institute, University of Newcastle, NSW 2308, Australia.

ABSTRACT
This chapter explores the possibility that capacitation and apoptosis are linked processes joined by their common dependence on the continued generation of reactive oxygen species (ROS). According to this model capacitation is initiated in spematozoa following their release into the female reproductive tract as a consequence of intracellular ROS generation, which stimulates intracellular cAMP generation, inhibits tyrosine phosphatase activity and enhances the formation of oxysterols prior to their removal from the sperm surface by albumin. The continued generation of ROS by capacitating populations of spermatozoa eventually overwhelms the limited capacity of these cells to protect themselves from oxidative stress. As a result the over-capacitation of spermatozoa leads to a state of senescence and the activation of a truncated intrinsic apoptotic cascade characterized by enhanced mitochondrial ROS generation, lipid peroxidation, motility loss, caspase activation and phosphatidylserine externalization. The latter may be particularly important in instructing phagocytic leukocytes that the removal of senescent, moribund spermatozoa should be a silent process unaccompanied by the generation of proinflammatory cytokines. These observations reveal the central role played by redox chemistry in defining the life and death of spermatozoa. A knowledge of these mechanisms may help us to engineer novel solutions to both support and preserve the functionality of these highly specialized cells.

No MeSH data available.


Related in: MedlinePlus