BACKGROUND Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss—via regulated cell death—occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction. OBJECTIVE AND RATIONALE Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life. SEARCH METHODS Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes. OUTCOMES Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress). WIDER IMPLICATIONS Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.

中文翻译：

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除了细胞凋亡：卵巢在整个发育和生命过程中其他受调节的细胞死亡途径的证据

背景技术调节细胞死亡是许多生理过程的基本组成部分。从子宫内的器官发生到成年期间的正常细胞更新，以及整个生命过程中受感染或受损细胞的消除。通过调节细胞死亡途径进行质量控制对于生殖系尤为重要，生殖系负责后代的产生。女性出生时就拥有全部生殖细胞，这些细胞位于称为卵泡的功能单元中。卵泡含有卵母细胞以及卵母细胞存活所必需的特化体细胞颗粒细胞。卵泡丢失（通过受调节的细胞死亡）发生在卵泡发育和生命的整个过程中，并且在暴露于各种环境和生活方式因素后可能会加速。人们认为，消除受损的卵泡对于确保只有最优质的卵母细胞才能用于繁殖是必要的。目的和基本原理了解触发和执行卵泡死亡的精确因素对于揭示卵泡禀赋最初是如何决定的，以及女性在整个青春期、生育期和卵巢衰老过程中如何维持卵泡数量至关重要。细胞凋亡被认为对于发育和生命各个阶段的卵巢稳态至关重要。然而，卵巢中其他细胞死亡途径的参与尚不清楚。本综述旨在总结有关卵巢细胞死亡调节因子的最新文献，特别关注非凋亡途径及其在卵巢发育和生殖生命的各个不同阶段的功能。检索方法 使用 PubMed 和 Google Scholar 对截至 2022 年 8 月发表的人类、动物和细胞研究进行全面的文献检索，使用以下检索词：卵子发生、卵泡形成、卵泡闭锁、卵母细胞丢失、卵母细胞凋亡、受调节的细胞死亡卵巢、卵巢非凋亡性细胞死亡、卵巢早衰、原始卵泡、卵母细胞质量控制、颗粒细胞死亡、卵巢自噬、卵母细胞自噬、卵巢坏死性凋亡、卵母细胞坏死性凋亡、卵巢焦亡、细胞焦亡卵母细胞中，卵巢中的parthanatos，卵母细胞中的parthanatos。结果哺乳动物细胞中有许多受调节的细胞死亡途径，包括细胞凋亡、自噬性细胞死亡、坏死性凋亡和细胞焦亡。然而，我们对不同生命阶段的每种卵巢细胞类型和卵泡类别中不同细胞死亡介质的了解仍然是正在进行的研究的来源。在这里，我们重点介绍非凋亡途径对卵巢发育和功能的贡献的最新证据。我们特别讨论了卵泡形成过程中自噬的参与以及自噬细胞死亡、坏死性凋亡、细胞焦亡和卵泡闭锁过程中的parthanatos的作用，特别是对生理应激源（例如氧化应激）的反应。更广泛的意义 更好地了解卵巢中每个受调节细胞死亡途径的作用对于了解卵巢发育以及整个生命周期中卵巢功能的维持至关重要。这些信息不仅与我们对女性内分泌健康、生殖健康和生育力的理解有关，而且还有助于确定新的生育力保存目标。