Abstract

BACKGROUND

Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.

OBJECTIVE AND RATIONALE

We summarize the functional roles of autophagy in the pre-testicular (hypothalamic–pituitary–testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.

SEARCH METHODS

In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: ‘autophagy’, ‘sperm’, ‘hypothalamic–pituitary–testis axis’, ‘spermatogenesis’, ‘spermatocytogenesis’, ‘spermatidogenesis’, ‘spermiogenesis’, ‘spermiation’, ‘sperm maturation’, ‘fertilization’, ‘capacitation’ and ‘acrosome’ in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as ‘bafilomycin A1’, ‘chloroquine’, ‘hydroxychloroquine’, ‘3-Methyl Adenine (3-MA)’, ‘lucanthone’, ‘wortmannin’ and autophagy activators such as ‘rapamycin’, ‘perifosine’, ‘metformin’ in combination with ‘disease’, ‘treatment’, ‘therapy’, ‘male infertility’ and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.

OUTCOMES

(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.

WIDER IMPLICATIONS

Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.

中文翻译：

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自噬：精子命运的多方面参与者

摘要

背景

自噬是细胞内降解和回收蛋白质和细胞器的分解代谢过程，以调节各种生理和病理事件，包括细胞分化和发育。新出现的数据表明，自噬与男性生殖密切相关，尤其是精子的生物合成和分解代谢过程。在精子的整个命运过程中，会发生一系列高度特化的细胞事件，包括睾丸前、睾丸和睾丸后事件。尽管如此，自噬在男性生殖中，尤其是在精子中，是起到保护作用还是有害作用的最基本问题仍不清楚。

目标和理由

我们总结了自噬在睾丸前（下丘脑-垂体-睾丸（HPG）轴）、睾丸（精子细胞发生、精子发生、精子发生、精子形成）和睾丸后（精子成熟和受精）过程中的功能作用。精子的命运。此外，确定了自噬对精子的作用和临床影响的关键机制，为男性​​不育症的治疗奠定了基础。

搜索方法

在这篇叙述性评论中，PubMed 数据库用于搜索同行评审的出版物，以使用以下术语总结自噬在精子命运中的功能作用：“自噬”、“精子”、“下丘脑-垂体-睾丸轴”、 “精子发生”、“精子发生”、“精子发生”、“精子发生”、“精子形成”、“精子成熟”、“受精”、“获能”和“顶体”与自噬相关蛋白结合。我们还使用自噬抑制剂的关键词，如“巴弗洛霉素 A1”、“氯喹”、“羟氯喹”、“3-甲基腺嘌呤 (3-MA)”、“硫蒽酮”，对自噬过程的临床影响进行了书目搜索。 ，“渥曼青霉素”和自噬激活剂，例如“雷帕霉素”、“perifosine”、“二甲双胍”与“疾病”、“治疗”、“疗法”相结合，“男性不育症”等术语。此外，还审查了主要和评论文章的参考列表以获取其他相关出版物。直到 2021 年 8 月的所有相关出版物都根据相关性、质量和时间表进行了严格评估和讨论。

结果

(i) 在睾丸前过程中，自噬相关基因参与 HPG 轴的调节；(ii) 在睾丸过程中，mTORC1 是自噬的主要通道，对精原干细胞 (SCC) 的增殖、分化、减数分裂进程、性染色体失活和精子发生至关重要。在精子发生过程中，自噬维持单倍体圆形精子细胞染色质体稳态以进行分化。在精子发生过程中，自噬参与顶体生物发生、鞭毛组装、头部整形和从伸长的精子细胞中去除细胞质。精子发生后，通过 PDLIM1，自噬协调顶端外质特化和基底外质特化来处理细胞骨架组装，控制精子在精子形成过程中的运动和释放。在睾丸后过程中，没有直接证据表明自噬参与获能过程。然而，自噬在受精过程中调节顶体反应、父系线粒体消除和膜细胞器的清除。

更广泛的影响

破译自噬在精子整个命运中的作用将为疾病治疗，特别是男性不育症的治疗提供有价值的见解。