TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α

Xingxing Zhu; Dongyan Shi; Xiaoqian Li; Weijuan Gong; Fengjiao Wu; Xuejiang Guo; Hui Xiao; Lixin Liu; Hong Zhou

doi:10.1016/j.cellsig.2015.12.002

TLR signalling affects sperm mitochondrial function and motility via phosphatidylinositol 3-kinase and glycogen synthase kinase-3α

Cell Signal. 2016 Mar;28(3):148-156. doi: 10.1016/j.cellsig.2015.12.002. Epub 2015 Dec 4.

Authors

Xingxing Zhu¹, Dongyan Shi², Xiaoqian Li², Weijuan Gong³, Fengjiao Wu², Xuejiang Guo¹, Hui Xiao⁴, Lixin Liu⁵, Hong Zhou⁶

Affiliations

¹ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
² Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
³ Department of Microbiology & Immunology, Yangzhou University, Yangzhou 225009, China.
⁴ Institute of Pasteur Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
⁵ Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
⁶ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China. Electronic address: [email protected].

PMID: 26658093
DOI: 10.1016/j.cellsig.2015.12.002

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.

Keywords: GSK3α; Mitochondrial function; PI3K; Sperm motility; TLR signalling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Androstadienes / pharmacology
Animals
Female
Glycogen Synthase Kinase 3 / metabolism*
Humans
Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
Interleukin-1 Receptor-Associated Kinases / metabolism
Lipopolysaccharides / pharmacology
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism*
Myeloid Differentiation Factor 88 / deficiency
Myeloid Differentiation Factor 88 / genetics
Myeloid Differentiation Factor 88 / metabolism
Phosphatidylinositol 3-Kinase / genetics
Phosphatidylinositol 3-Kinase / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation / drug effects
Signal Transduction / drug effects
Sperm Motility / drug effects
Spermatozoa / metabolism*
Toll-Like Receptors / agonists
Toll-Like Receptors / metabolism*
Wortmannin
Zymosan / pharmacology

Substances

Androstadienes
Lipopolysaccharides
Myeloid Differentiation Factor 88
Phosphoinositide-3 Kinase Inhibitors
Toll-Like Receptors
Adenosine Triphosphate
Zymosan
Phosphatidylinositol 3-Kinase
Interleukin-1 Receptor-Associated Kinases
Irak4 protein, mouse
Glycogen Synthase Kinase 3
glycogen synthase kinase 3 alpha
Wortmannin