自噬对精子发生及活力的影响
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摘要
精子数量减少、活力低下及精子畸形等是造成男性不育的重要原因,其中很多病症的发病机制尚未阐明。自噬是一种进化上高度保守的代谢过程。在正常生理条件及不利环境下,自噬在生精细胞中都发挥着重要作用。一方面,自噬可将大多数长寿命蛋白质和细胞器降解,从而维持生精细胞内稳态、保障精母细胞减数分裂及精子形成、提高精子活力。另一方面,自噬水平过度也会导致蛋白质的过度消耗及细胞器损伤,使细胞功能紊乱,最终引起精子数量减少,精子生成缺陷及精子活力降低。本文综述了自噬对精子发生及活力影响的相关研究,以期为男性不育的治疗提供新的靶点。
Decreased sperm count,low sperm motility and sperm malformation are important factors of male infertility,but their pathogenic mechanisms have not yet been elucidated.Autophagy is an evolutionarily highly conservative cellular process and plays an important role in spermatogenic cells in both normal physiological and adverse conditions.On the one hand,autophagy can degrade the majority of long-lived proteins and organelles to maintain the intracellular homeostasis of spermatogenic cells,the meiosis of spermatocytes and spermiogenesis,and improve sperm motility.On the other hand,excessive autophagy can lead to excessive consumption of proteins and damage to organelles,induce cellular dysfunction,and result in sperm count reduction,spermatogenic defects,and low sperm motility.This review presents an overview of the recent studies on the influences of autophagy on spermatogenesis and sperm motility,aiming for some new therapeutic targets for male infertility.
Decreased sperm count,low sperm motility and sperm malformation are important factors of male infertility,but their pathogenic mechanisms have not yet been elucidated.Autophagy is an evolutionarily highly conservative cellular process and plays an important role in spermatogenic cells in both normal physiological and adverse conditions.On the one hand,autophagy can degrade the majority of long-lived proteins and organelles to maintain the intracellular homeostasis of spermatogenic cells,the meiosis of spermatocytes and spermiogenesis,and improve sperm motility.On the other hand,excessive autophagy can lead to excessive consumption of proteins and damage to organelles,induce cellular dysfunction,and result in sperm count reduction,spermatogenic defects,and low sperm motility.This review presents an overview of the recent studies on the influences of autophagy on spermatogenesis and sperm motility,aiming for some new therapeutic targets for male infertility.
引文
[1]Matzuk MM,Lamb DJ.The biology of infertility:Research advances and clinical challenges.Nat Med,2008,14(11):1197-1213.
[2]Liu B,Wang P,Wang Z,et al.Analysis and difference of voltage-dependent anion channel m RNA in ejaculated spermatozoa from normozoospermic fertile donors and infertile patients with idiopathic asthenozoospermia.J Assist Reprod Genet,2010,27(12):719-724.
[3]Chen H,Ruan YC,Xu WM,et al.Regulation of male fertility by CFTR and implications in male infertility.Hum Reprod Update,2012,18(6):703-713.
[4]秦正红主编.自噬---生物学与疾病·基础卷(第2版),北京:科学出版社.2015.101-107.
[5]朱倩,崔毓桂.精子发生的调节机制及其进展.生殖医学杂志,2016,25(4):278-284.
[6]Tegelenbosch RA,de Rooij DG.A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1hybrid mouse.Mutat Res,1993,290(2):193-200.
[7]谭俊玲.小鼠生精细胞与支持细胞自噬与自噬诱因的初步研究(硕士论文).济南:山东大学,2013.46-49.
[8]Bustamante-Marín X,Quiroga C,Lavandero S,et al.Apoptosis,necrosis and autophagy are influenced by metabolic energy sources in cultured rat spermatocytes.Apoptosis,2012,17(6):539-550.
[9]Liu ML,Wang JL,Wei J,et al.Tri-ortho-cresyl phosphate induces autophagy of rat spermatogonial stem cells.Reproduction,2015,149(2):163-170.
[10]Xu LL,Liu ML,Wang JL,et al.Saligenin cyclic-o-tolyl phosphate(SCOTP)induces autophagy of rat spermatogonial stem cells.Reprod Toxicol,2016,60:62-68.
[11]Liu K,Zhang G,Wang Z,et al.The protective effect of autophagy on mouse spermatocyte derived cells exposure to 1800 MHz radiofrequency electromagnetic radiation.Toxicol Lett,2014,228(3):216-224.
[12]Mancilla H,Maldonado R,Cereceda K,et al.Glutathione depletion induces spermatogonial cell autophagy.J Cell Biochem,2015,116(10):2283-2292.
[13]Han SP,Zhou DX,Lin P,et al.Formaldehyde exposure induces autophagy in testicular tissues of adult male rats.Environ Toxicol,2015,30(3):323-331.
[14]Brar GA,Yassour M,Friedman N,et al.High-resolution view of the yeast meiotic program revealed by ribosome profiling.Science,2012,335(6068):552-557.
[15]Mc Nally K,Berg E,Cortes DB,et al.Katanin maintains meiotic metaphase chromosome alignment and spindle structure in vivo and has multiple effects on microtubules in vitro.Mol Biol Cell,2014,25(7):1037-1049.
[16]Kabeya Y,Mizushima N,Ueno T,et al.LC3,a mammalian homologue of yeast Apg8p,is localized in autophagosome membranes after processing.EMBO Mol Med,2000,19(21):5720-5728.
[17]Wen FP,Guo YS,Hu Y1,et al.Distinct temporal requirements for autophagy and the proteasome in yeast meiosis.Autophagy,2016,12(4):671-688.
[18]Jao CC,Ragusa MJ,Stanley,et al.A HORMA domain in Atg13mediates PI3-kinase recruitment in autophagy.PNAS,2013,110(14):5486-5491.
[19]Gallardo Bolanos JM,Miro Moran A,Balao da Silva CM,et al.Autophagy and apoptosis have a role in the survival or death of stallion spermatozoa during conservation in refrigeration.PLo SOne,2012,7(1):e30688.
[20]Wang H,Wan H,Li X,et al.Atg7 is required for acrosome biogenesis during spermatogenesis in mice.Cell Res,2014,24(7):852-869.
[21]Shang Y,Wang H,Jia P,et al.Autophagy regulates spermatid differentiation via degradation of PDLIM1.Autophagy,2016,12(9):1575-1592.
[22]Zhuo C,Ji Y,Chen Z,et al.Proteomics analysis of autophagydeficient Atg7-/-MEFs reveals a close relationship between F-actin and autophagy.Biochem Biophys Res Commun,2013,437(3):482-488.
[23]Liu C,Wang H,Shang Y,et al.Autophagy is required for ectoplasmic specialization assembly in sertoli cells.Autophagy,2016,12(5):814-832.
[24]Liu SJ,Huang LX,Geng YQ,et al.Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats.Mol Med Rep,2017,16(4):4029-4037.
[25]Mu Y,Yan WJ,Yin TL,et al.Diet-induced obesity impairs spermatogenesis:A potential role for autophagy.Sci Rep,2017,7:43475.
[26]Pelliccione F,Micillo A,Cordeschi G,et al.Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia.Fertil Steril,2011,95(2):641-646.
[27]Rodrigues P,Limback D,Mc Ginnis LK,et al.Multiple mechanisms of germ cell loss in the perinatal mouse ovary.Reproduction,2009,137(4):709-720.
[28]Aparicio IM,Martin Munoz P,Salido GM,et al.Theautophagyrelated protein LC3 is processed in stallion spermatozoa during short and long-term storage and the related stressful conditions.Animal,2016,10(7):1182-1191.
[29]Aparicio IM,Espino J,Bejarano I,et al.Autophagy-related proteins are functionally active in human spermatozoa and may be involved in the regulation of cell survival and motility.Sci Rep,2016,6:33647.
[30]Zhang J,Zhang X,Liu Y,et al.Leucine mediates autophagosome-lysosome fusion and improves sperm motility by activating the PI3K/Akt pathway.Oncotarget,2017,8(67):111807-111818.
[31]Norman C,Gombe S.Stimulatory effect of the lysosomal stabilizer,chloroquine,on the respiration and motility of fresh and aged bovine spermatozoa.J Reprod Fertil,1975,44(3):481-486.
[32]Egbunike GN.Effect of chloroquine on the motility and acetylcholinesterase activity of porcine spermatozoa during epididymal maturation.Andrologia,1982,14(6):503-508.
[33]Zhang J,Ma WG,Xie BY,et al.Beneficial effect and potential molecular mechanism of chloroquine on sperm motility and fertilizing ability in yellow catfish.Aquaculture,2017,468:307-313.
[34]Adeeko AO,Dada OA.Chloroquine reduces fertilizing capacity of epididyma sperm in rats.Afr J Med Sci,1998,27(1-2):63-64.
[35]Okanlawon AO,Noronha CC,Ashiru OA.An investigation into the effects of chloroquine on fertility of male rats.West Afr JMed,1993,12(2):118-121.
[36]Hargreaves CA,Rogers S,Hills F,et al.Effects of co-trimoxazole,erythromycin,amoxicillin,tetracycline and chloroquine on sperm function in vitro.Hum Reprod,1998,13(7),1878-1886.
[37]Li R,Luo X,Zhu Y,et al.ATM signals to AMPK to promote autophagy and positively regulate DNA damage in response to cadmium-induced ROS in mouse spermatocytes.Environ Pollut,2017,231(Pt 2):1560-1568.
[38]Wang HL,Fan SS,Pang M,et al.The ankyrin repeat domain49(ANKRD49)augments autophagy of serum-starved GC-1 cells through the NF-κB pathway.PLo S One,2015,10(6):e0128551.
[39]Zhang G,Liu K,Ling X,et al.DBP-induced endoplasmic reticulum stress in male germ cells causes autophagy,which has a cytoprotective role against apoptosis in vitro and in vivo.Toxicol Lett,2016,245:86-98.
[40]Gu YP,Yang XM,Duan ZH,et al.Squid ink polysaccharide prevents autophagy and oxidative stress affected by cyclophosphamide in Leydig cells of mice:A pilot study.Iran J Basic Med Sci,2017,20(11):1194-1199.
[41]Zhu B,Zheng YF,Zhang YY,et al.Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis.J Zhejiang Univ Sci B,2015,16(9):780-787.
[42]陈绪军.五子衍宗丸治疗少弱精子症的疗效观察.实用临床医药杂志,2011,15(11):116-120.
[43]秦茂.基于支持细胞线粒体自噬途径研究五子衍宗丸改善生精功能机理(硕士论文).北京:北京中医药大学,2016:1-15.
[2]Liu B,Wang P,Wang Z,et al.Analysis and difference of voltage-dependent anion channel m RNA in ejaculated spermatozoa from normozoospermic fertile donors and infertile patients with idiopathic asthenozoospermia.J Assist Reprod Genet,2010,27(12):719-724.
[3]Chen H,Ruan YC,Xu WM,et al.Regulation of male fertility by CFTR and implications in male infertility.Hum Reprod Update,2012,18(6):703-713.
[4]秦正红主编.自噬---生物学与疾病·基础卷(第2版),北京:科学出版社.2015.101-107.
[5]朱倩,崔毓桂.精子发生的调节机制及其进展.生殖医学杂志,2016,25(4):278-284.
[6]Tegelenbosch RA,de Rooij DG.A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1hybrid mouse.Mutat Res,1993,290(2):193-200.
[7]谭俊玲.小鼠生精细胞与支持细胞自噬与自噬诱因的初步研究(硕士论文).济南:山东大学,2013.46-49.
[8]Bustamante-Marín X,Quiroga C,Lavandero S,et al.Apoptosis,necrosis and autophagy are influenced by metabolic energy sources in cultured rat spermatocytes.Apoptosis,2012,17(6):539-550.
[9]Liu ML,Wang JL,Wei J,et al.Tri-ortho-cresyl phosphate induces autophagy of rat spermatogonial stem cells.Reproduction,2015,149(2):163-170.
[10]Xu LL,Liu ML,Wang JL,et al.Saligenin cyclic-o-tolyl phosphate(SCOTP)induces autophagy of rat spermatogonial stem cells.Reprod Toxicol,2016,60:62-68.
[11]Liu K,Zhang G,Wang Z,et al.The protective effect of autophagy on mouse spermatocyte derived cells exposure to 1800 MHz radiofrequency electromagnetic radiation.Toxicol Lett,2014,228(3):216-224.
[12]Mancilla H,Maldonado R,Cereceda K,et al.Glutathione depletion induces spermatogonial cell autophagy.J Cell Biochem,2015,116(10):2283-2292.
[13]Han SP,Zhou DX,Lin P,et al.Formaldehyde exposure induces autophagy in testicular tissues of adult male rats.Environ Toxicol,2015,30(3):323-331.
[14]Brar GA,Yassour M,Friedman N,et al.High-resolution view of the yeast meiotic program revealed by ribosome profiling.Science,2012,335(6068):552-557.
[15]Mc Nally K,Berg E,Cortes DB,et al.Katanin maintains meiotic metaphase chromosome alignment and spindle structure in vivo and has multiple effects on microtubules in vitro.Mol Biol Cell,2014,25(7):1037-1049.
[16]Kabeya Y,Mizushima N,Ueno T,et al.LC3,a mammalian homologue of yeast Apg8p,is localized in autophagosome membranes after processing.EMBO Mol Med,2000,19(21):5720-5728.
[17]Wen FP,Guo YS,Hu Y1,et al.Distinct temporal requirements for autophagy and the proteasome in yeast meiosis.Autophagy,2016,12(4):671-688.
[18]Jao CC,Ragusa MJ,Stanley,et al.A HORMA domain in Atg13mediates PI3-kinase recruitment in autophagy.PNAS,2013,110(14):5486-5491.
[19]Gallardo Bolanos JM,Miro Moran A,Balao da Silva CM,et al.Autophagy and apoptosis have a role in the survival or death of stallion spermatozoa during conservation in refrigeration.PLo SOne,2012,7(1):e30688.
[20]Wang H,Wan H,Li X,et al.Atg7 is required for acrosome biogenesis during spermatogenesis in mice.Cell Res,2014,24(7):852-869.
[21]Shang Y,Wang H,Jia P,et al.Autophagy regulates spermatid differentiation via degradation of PDLIM1.Autophagy,2016,12(9):1575-1592.
[22]Zhuo C,Ji Y,Chen Z,et al.Proteomics analysis of autophagydeficient Atg7-/-MEFs reveals a close relationship between F-actin and autophagy.Biochem Biophys Res Commun,2013,437(3):482-488.
[23]Liu C,Wang H,Shang Y,et al.Autophagy is required for ectoplasmic specialization assembly in sertoli cells.Autophagy,2016,12(5):814-832.
[24]Liu SJ,Huang LX,Geng YQ,et al.Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats.Mol Med Rep,2017,16(4):4029-4037.
[25]Mu Y,Yan WJ,Yin TL,et al.Diet-induced obesity impairs spermatogenesis:A potential role for autophagy.Sci Rep,2017,7:43475.
[26]Pelliccione F,Micillo A,Cordeschi G,et al.Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia.Fertil Steril,2011,95(2):641-646.
[27]Rodrigues P,Limback D,Mc Ginnis LK,et al.Multiple mechanisms of germ cell loss in the perinatal mouse ovary.Reproduction,2009,137(4):709-720.
[28]Aparicio IM,Martin Munoz P,Salido GM,et al.Theautophagyrelated protein LC3 is processed in stallion spermatozoa during short and long-term storage and the related stressful conditions.Animal,2016,10(7):1182-1191.
[29]Aparicio IM,Espino J,Bejarano I,et al.Autophagy-related proteins are functionally active in human spermatozoa and may be involved in the regulation of cell survival and motility.Sci Rep,2016,6:33647.
[30]Zhang J,Zhang X,Liu Y,et al.Leucine mediates autophagosome-lysosome fusion and improves sperm motility by activating the PI3K/Akt pathway.Oncotarget,2017,8(67):111807-111818.
[31]Norman C,Gombe S.Stimulatory effect of the lysosomal stabilizer,chloroquine,on the respiration and motility of fresh and aged bovine spermatozoa.J Reprod Fertil,1975,44(3):481-486.
[32]Egbunike GN.Effect of chloroquine on the motility and acetylcholinesterase activity of porcine spermatozoa during epididymal maturation.Andrologia,1982,14(6):503-508.
[33]Zhang J,Ma WG,Xie BY,et al.Beneficial effect and potential molecular mechanism of chloroquine on sperm motility and fertilizing ability in yellow catfish.Aquaculture,2017,468:307-313.
[34]Adeeko AO,Dada OA.Chloroquine reduces fertilizing capacity of epididyma sperm in rats.Afr J Med Sci,1998,27(1-2):63-64.
[35]Okanlawon AO,Noronha CC,Ashiru OA.An investigation into the effects of chloroquine on fertility of male rats.West Afr JMed,1993,12(2):118-121.
[36]Hargreaves CA,Rogers S,Hills F,et al.Effects of co-trimoxazole,erythromycin,amoxicillin,tetracycline and chloroquine on sperm function in vitro.Hum Reprod,1998,13(7),1878-1886.
[37]Li R,Luo X,Zhu Y,et al.ATM signals to AMPK to promote autophagy and positively regulate DNA damage in response to cadmium-induced ROS in mouse spermatocytes.Environ Pollut,2017,231(Pt 2):1560-1568.
[38]Wang HL,Fan SS,Pang M,et al.The ankyrin repeat domain49(ANKRD49)augments autophagy of serum-starved GC-1 cells through the NF-κB pathway.PLo S One,2015,10(6):e0128551.
[39]Zhang G,Liu K,Ling X,et al.DBP-induced endoplasmic reticulum stress in male germ cells causes autophagy,which has a cytoprotective role against apoptosis in vitro and in vivo.Toxicol Lett,2016,245:86-98.
[40]Gu YP,Yang XM,Duan ZH,et al.Squid ink polysaccharide prevents autophagy and oxidative stress affected by cyclophosphamide in Leydig cells of mice:A pilot study.Iran J Basic Med Sci,2017,20(11):1194-1199.
[41]Zhu B,Zheng YF,Zhang YY,et al.Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis.J Zhejiang Univ Sci B,2015,16(9):780-787.
[42]陈绪军.五子衍宗丸治疗少弱精子症的疗效观察.实用临床医药杂志,2011,15(11):116-120.
[43]秦茂.基于支持细胞线粒体自噬途径研究五子衍宗丸改善生精功能机理(硕士论文).北京:北京中医药大学,2016:1-15.