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Review
. 2023 Jul 5;29(4):434-456.
doi: 10.1093/humupd/dmad005.

Beyond apoptosis: evidence of other regulated cell death pathways in the ovary throughout development and life

Jessica M Stringer  1 , Lauren R Alesi  1 , Amy L Winship  1 , Karla J Hutt  1
Affiliations
Review

Beyond apoptosis: evidence of other regulated cell death pathways in the ovary throughout development and life

Jessica M Stringer et al. Hum Reprod Update. .

Abstract

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.

Keywords: apoptosis; autophagy; fertility; granulosa cell; necroptosis; oocyte; ovary; parthanatos; pyroptosis; regulated cell death.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial, or other interests.

Figures

Graphical Abstract
Graphical Abstract
Although apoptosis has well-established roles in regulating ovarian follicle number across the lifespan, recent evidence suggests autophagic cell death, necroptosis, pyroptosis, and parthanatos also contribute.
Figure 1.
Figure 1.
Types of cell death active within the ovary throughout various stages of development. The regulated cell death pathways apoptosis (intrinsic and extrinsic), autophagic cell death, necroptosis, pyroptosis, and parthanatos are all active within the ovary in numerous species, including humans. The ovarian cell type and stage of development in which evidence has been published is summarized. Figure created using BioRender.
Figure 2.
Figure 2.
Overview of regulated cell death pathways. A summary of each of the well-described regulated cell death pathways—apoptosis (intrinsic and extrinsic), autophagic cell death, necroptosis, pyroptosis, and parthanatos. Intrinsic apoptosis: After an intrinsic lethal signal occurs (e.g. DNA damage), BH3-only proteins activate BAX and BAK either directly, or indirectly by binding and inhibiting BCL-2 proteins. Mitochondrial outer membrane permeabilization (MOMP) then occurs, which releases cytochrome C (Cyt C) and SMAC, the latter of which can inhibit apoptosis. The apoptosome is then formed, leading to caspase-9 activation, subsequent caspase-3 and -7 activation, and initiation of apoptosis. Extrinsic apoptosis: Once death receptors (e.g. TNFR1, FAS, or TRAIL-R) detect an extrinsic lethal signal, this receptor associates with pro-caspase-8 and -10 to form complex I. Complex IIa is subsequently formed, which leads to caspase-8 and -10 activation. Apoptosis is then initiated either directly, via direct cleavage of caspase-3 and -7; or indirectly, via cleavage of BID into tBID and subsequent activation of BAX and BAK. Necroptosis: Following an extrinsic lethal signal and in the absence of caspase-8 activation, complex IIb (i.e. the necrosome) is formed. This leads to phosphorylation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3, which phosphorylate and activate mixed lineage kinase domain-like pseudokinase (MLKL). MLKL then forms a complex, resulting in release of cytokines, chemokines, and damage-associated molecular patterns (DAMPS). Ultimately, this results in inflammation and necroptosis of the cell. Pyroptosis: Once toll-like receptors (e.g. TLR4) detect an extrinsic lethal signal, nuclear factor kappa B (NF-κB) signalling is activated. This results in inflammasome formation and subsequent caspase-1 activation. Then, pro-IL-1β is converted into IL-1β, and gasdermin D (GSDMD) is cleaved into N-GSDMD fragments. This leads to inflammation and pyroptosis of the cell. Parthanatos: Once an intrinsic lethal signal occurs (e.g. excessive reactive oxygen species accumulation), poly[ADP-ribose] polymerase 1 (PARP-1) becomes activated. If PARP-1 overactivation occurs, this can lead to accumulation of PAR polymer and translocation of apoptosis inhibitory factor (AIF) from mitochondria. AIF forms a complex with macrophage migration inhibitory factor (MIF), which re-enters the nucleus. Ultimately, this leads to DNA fragmentation and parthanatos of the cell. Autophagic cell death: Beclin-1 normally exists in a complex with BCL-2 proteins. Once these have been phosphorylated and inactivated, free Beclin-1 can then initiate autophagy. Autophagy involves fusion of the autophagosome and lysosome to form the autolysosome, which then degrades and recycles intracellular components. This can lead to cell survival, but sometimes can cause autophagy-mediated cell death (by activating either apoptosis or necroptosis) or autophagy-dependent cell death (i.e. cell death without apoptosis or necroptosis). Figure created using BioRender.
Figure 3.
Figure 3.
Timing of regulated cell death across the lifespan within the ovary in women. It is well-defined that multiple windows of increased germ cell loss across the female lifespan. These include immediately prior to birth and puberty. After puberty, there is a consistent decline in germ cell number across reproductive life, until menopause ensues. However, spikes in loss can be induced in response to endogenous and/or exogenous insults. Figure created using BioRender.
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