The lysosome is the most acidic membrane-bound intracellular organelle.Lysosomal acidity is primarily maintained by vacuolar H+-ATPase(V-ATPase)and counter ion channels.There are>60 hydrolytic enzymes in the lysoso...The lysosome is the most acidic membrane-bound intracellular organelle.Lysosomal acidity is primarily maintained by vacuolar H+-ATPase(V-ATPase)and counter ion channels.There are>60 hydrolytic enzymes in the lysosome for its fundamental digestive role.Lysosomes also play important roles in endocytosis,exocytosis,autophagy,and cell death.Studies that have implicated roles of lysosomes in the female reproductive system are reviewed here.In the ovary,lysosomes are implicated in the preparation of free cholesterol for steroidogenesis and degradation of regulators of steroidogenesis,regulation of follicular atresia,follicle rupture during ovulation,luteal cell survival,and luteal regression.In the oviduct,lysosomes are involved in endocytosis of both serum and oviductal luminal components.In the uterus during the menstrual/estrous cycle,lysosomes are associated with endometrial secretion,apoptosis,and menstruation.In the uterus during early pregnancy,lysosomes are involved in the temporal and directional changes of endocytosis,uterine epithelial acidification upon embryo implantation initiation,and embryo-maternal mutual communications via extracellular vesicles.In the placenta,lysosomes are implicated in nutrient transport and placental separation from the uterus for parturition.In the mammary gland,lysosomes are important for mammary gland development and involution.These findings suggest/demonstrate functions of lysosomes in multiple processes of female reproduction,from ovulation to ovarian steroidogenesis for pregnancy maintenance,and from essential in utero nurturing of developing embryos/fetuses via embryo/fetal-maternal communications,to optional postpartum nurturing of newborns via lactation.Future studies using genetically or modified animal models and pharmacological approaches will provide novel insights into the functions and mechanisms of lysosomes in the mammalian female reproductive system.展开更多
Objective:FemaleMcoln1^(-/-)mice exhibit progressive progesterone(P4)deficiency,luteal cell degeneration,and premature embryo implantation failure at 5 months old.We attempted to rescue embryo implantation in non-virg...Objective:FemaleMcoln1^(-/-)mice exhibit progressive progesterone(P4)deficiency,luteal cell degeneration,and premature embryo implantation failure at 5 months old.We attempted to rescue embryo implantation in non-virginMcoln1^(-/-)mice(5-6 months old)with exogenous P4 treatment on days 1.5 post-coitum(D1.5),D2.5,and D3.5,and observed partially restored luteal cell morphology on D4.5,but unexpectedly found 17β-estradiol(E2)contamination in the P4 working solution.In this study,we aim to investigate exogenous P4 and/or E2 for the partial recovery of luteal cell morphology in infertileMcoln1^(-/-)mice.Methods:Control and non-virginMcoln1^(-/-)mice(5-6 months old)were treated with newly ordered vehicle,P4,E2,or P4+E2 on D1.5 and D2.5 and dissected on D3.5 for P4 and E2 measurements,ovary histology,immunofluorescence,lipid droplet staining,and transmission electron microscopy.Results:E2 treatment significantly increased serum P4 levels in D3.5Mcoln1^(-/-)mice.E2 and P4+E2 treatments,but not P4 treatment alone,largely improved the morphology of D3.5Mcoln1^(-/-)corpora lutea,indicated by a more contiguous web-like collagen IV expression pattern,increased heat shock protein 60 expression,and reduced accumulation of large lipid droplets.Transmission electron microscopy revealed extremely enlarged autophagosomes and lipid droplets,lysosomes with lamellar structures,and mitochondria with reduced cristae in vehicle-treated D3.5Mcoln1^(-/-)luteal cells,while in E2-treated D3.5Mcoln1^(-/-)luteal cells,extremely enlarged autophagosomes and lipid droplets were reduced,indicating improved luteal cell ultrastructure.Conclusion:These findings reveal protective effects of high levels of exogenous E2 on P4 production and lysosomal function inMcoln1^(-/-)luteal cells.展开更多
基金support from Interdisciplinary Toxicology Program,Department of Physiology and Pharmacology,College of Veterinary Medicine,and Office of the Vice President for Research at University of Georgia,as well as the National Institutes of Health(R01HD065939(co-funded by ORWH and NICHD),R03HD097384,and R03HD100652).
文摘The lysosome is the most acidic membrane-bound intracellular organelle.Lysosomal acidity is primarily maintained by vacuolar H+-ATPase(V-ATPase)and counter ion channels.There are>60 hydrolytic enzymes in the lysosome for its fundamental digestive role.Lysosomes also play important roles in endocytosis,exocytosis,autophagy,and cell death.Studies that have implicated roles of lysosomes in the female reproductive system are reviewed here.In the ovary,lysosomes are implicated in the preparation of free cholesterol for steroidogenesis and degradation of regulators of steroidogenesis,regulation of follicular atresia,follicle rupture during ovulation,luteal cell survival,and luteal regression.In the oviduct,lysosomes are involved in endocytosis of both serum and oviductal luminal components.In the uterus during the menstrual/estrous cycle,lysosomes are associated with endometrial secretion,apoptosis,and menstruation.In the uterus during early pregnancy,lysosomes are involved in the temporal and directional changes of endocytosis,uterine epithelial acidification upon embryo implantation initiation,and embryo-maternal mutual communications via extracellular vesicles.In the placenta,lysosomes are implicated in nutrient transport and placental separation from the uterus for parturition.In the mammary gland,lysosomes are important for mammary gland development and involution.These findings suggest/demonstrate functions of lysosomes in multiple processes of female reproduction,from ovulation to ovarian steroidogenesis for pregnancy maintenance,and from essential in utero nurturing of developing embryos/fetuses via embryo/fetal-maternal communications,to optional postpartum nurturing of newborns via lactation.Future studies using genetically or modified animal models and pharmacological approaches will provide novel insights into the functions and mechanisms of lysosomes in the mammalian female reproductive system.
基金the Offfce of the Vice President for Research,Interdisciplinary Toxicology Program,and Department of Physiology and Pharmacology at the University of Georgia,and the National Institutes of Health(grants NIH R01HD065939[co-funded by ORWH and NICHD],R03HD097384,and R03 HD100652 to X.Y.)for ffnancial supportSerum P4 and E2 levels were determined at The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core,which is supported by the Eunice Kennedy Shriver NICHD/NIH(NCTRI)Grant P50-HD28934.
文摘Objective:FemaleMcoln1^(-/-)mice exhibit progressive progesterone(P4)deficiency,luteal cell degeneration,and premature embryo implantation failure at 5 months old.We attempted to rescue embryo implantation in non-virginMcoln1^(-/-)mice(5-6 months old)with exogenous P4 treatment on days 1.5 post-coitum(D1.5),D2.5,and D3.5,and observed partially restored luteal cell morphology on D4.5,but unexpectedly found 17β-estradiol(E2)contamination in the P4 working solution.In this study,we aim to investigate exogenous P4 and/or E2 for the partial recovery of luteal cell morphology in infertileMcoln1^(-/-)mice.Methods:Control and non-virginMcoln1^(-/-)mice(5-6 months old)were treated with newly ordered vehicle,P4,E2,or P4+E2 on D1.5 and D2.5 and dissected on D3.5 for P4 and E2 measurements,ovary histology,immunofluorescence,lipid droplet staining,and transmission electron microscopy.Results:E2 treatment significantly increased serum P4 levels in D3.5Mcoln1^(-/-)mice.E2 and P4+E2 treatments,but not P4 treatment alone,largely improved the morphology of D3.5Mcoln1^(-/-)corpora lutea,indicated by a more contiguous web-like collagen IV expression pattern,increased heat shock protein 60 expression,and reduced accumulation of large lipid droplets.Transmission electron microscopy revealed extremely enlarged autophagosomes and lipid droplets,lysosomes with lamellar structures,and mitochondria with reduced cristae in vehicle-treated D3.5Mcoln1^(-/-)luteal cells,while in E2-treated D3.5Mcoln1^(-/-)luteal cells,extremely enlarged autophagosomes and lipid droplets were reduced,indicating improved luteal cell ultrastructure.Conclusion:These findings reveal protective effects of high levels of exogenous E2 on P4 production and lysosomal function inMcoln1^(-/-)luteal cells.
