title: Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa.
abstract: Human spermatozoa are characterized by poor functionality and abundant DNA damage that collude to generate the high incidences of male infertility and miscarriage seen in our species. Although apoptosis has been suggested as a possible cause of poor sperm quality, the ability of these cells to enter an apoptotic state and the factors that might trigger such an event are unresolved. In the present study we provide evidence that the commitment of these cells to apoptosis is negatively regulated by PI3K (phosphoinositide 3-kinase)/AKT. If PI3K activity is inhibited, then spermatozoa default to an apoptotic cascade characterized by rapid motility loss, mitochondrial reactive oxygen species generation, caspase activation in the cytosol, annexin V binding to the cell surface, cytoplasmic vacuolization and oxidative DNA damage. However, the specialized physical architecture of spermatozoa subsequently prevents endonucleases activated during this process from penetrating the sperm nucleus and cleaving the DNA. As a result, DNA fragmentation does not occur as a direct result of apoptosis in spermatozoa as it does in somatic cells, even though oxidative DNA adducts can clearly be detected. We propose that this unusual truncated apoptotic cascade prepares spermatozoa for silent phagocytosis within the female tract and prevents DNA-damaged spermatozoa from participating in fertilization.
authors.affiliation: Discipline of Biological Sciences and ARC Centre of Excellence in Biotechnology and Development, Faculty of Science and IT, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Koppers
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mitchell
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Minjie
authors.initials: M
authors.lastname: Lin
authors.forename: R John
authors.initials: RJ
authors.lastname: Aitken
mesh_terms: D017209:Apoptosis / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013081:Sperm Motility / Q000235:genetics; D013094:Spermatozoa / Q000502:physiology*
chemical_list: D058539:Phosphatidylinositol 3-Kinase