title: TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α.
abstract: Infection in male and female genital tracts can lead to infertility. The underlying mechanisms of this process remain unclear. Toll-like receptors (TLRs) recognize conserved structures and respond to pathogens by initiating signals that activate inflammatory gene transcription. Here, we demonstrate that TLR activation in sperm reduces sperm motility via signalling through myeloid differentiation factor 88 (MyD88), phosphatidylinositol 3-kinase (PI3K), and glycogen synthase kinase (GSK)-3α. Upon TLR activation, phosphorylated forms of PI3K and GSK3α were detected in the mitochondria, and the mitochondrial membrane potential was impaired in sperm. In addition, mitochondrial ATP levels were decreased after TLR agonist stimulation. Furthermore, blocking PI3K or GSK3α activation abrogated these effects and reversed the TLR-induced reduction in sperm motility. These results identify a previously unrecognized TLR signalling pathway that leads to dysfunctional sperm mitochondria, which reduce sperm motility. Our study reveals a novel mechanism by which pathogenic infection affects sperm motility and possibly leads to infertility.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology & Immunology, Yangzhou University, Yangzhou 225009, China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuejiang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute of Pasteur Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Lixin
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. Electronic address: hzhou@njmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D000077191:Wortmannin; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D015054:Zymosan; D058539:Phosphatidylinositol 3-Kinase; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D000077191:Wortmannin
keywords: GSK3α; Mitochondrial function; PI3K; Sperm motility; TLR signalling