Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype

Woo, Jeong-Hwa; Choi, Youn Seok; Choi, Jung‐Hye

doi:10.3390/biomedicines8110454

Cited by 25 publications

(21 citation statements)

References 56 publications

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“…However, our retrospective analysis showed that oocyte quality was poorer in patients with OE than those with non-ovarian endometriosis (Table 1 ). Iron overload in the peritoneal fluid and FF of EMs patients is an important factor that leads to ectopic tissue proliferation and damage to oocytes [ 8 , 27 ], but the specific mechanism in which iron overload in the FF affects granulosa cells and oocytes has not been fully elucidated. Considering that follicles close to the OE lesion tissues exhibit higher total iron levels and lower oocyte retrieval rates than follicles in healthy ovaries [ 28 ], iron overload in the OE may impair oocyte maturation and function by affecting granulosa cells close to the lesion and further mediate the release of abnormal exosomes of granulosa cells.…”

Section: Discussionmentioning

confidence: 99%

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Ni¹,

Li²,

Song³

et al. 2022

Cell Death Dis

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Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.

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Section: Discussionmentioning

confidence: 99%

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Ni¹,

Li²,

Song³

et al. 2022

Cell Death Dis

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“…Harvested tissue is suspended in 200 -500 µl of solution before injection into the peritoneal cavity. Solutions vary between studies, and include saline (Pittaluga et al, 2010;Uegaki et al, 2015;Ruiz et al, 2016;Dodds et al, 2017;Sanchez et al, 2017;Yan et al, 2019;Kim et al, 2020), Hank's Balanced Salt Solution (HBSS) (Fattori et al, 2020), phosphate-buffered saline (PBS) (Bacci et al, 2009;Chen et al, 2009;Altan et al, 2010;Jensen et al, 2010;Wieser et al, 2012;Tomio et al, 2013;Greaves et al, 2014;Heard et al, 2016;Yuan et al, 2018;Horne et al, 2019;Woo et al, 2020), and warmed Dulbecco's Modified Eagle Medium (DMEM) (Nowak et al, 2008). The solutions chosen mimic the salinity and pH of the peritoneal cavity and maintain viability of the uterine tissue.…”

Section: Intraperitoneal Injectionmentioning

confidence: 99%

Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

et al. 2022

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Endometriosis is a prevalent gynecologic condition associated with pelvic pain and infertility characterized by the implantation and growth of endometrial tissue displaced into the pelvis via retrograde menstruation. The mouse is a molecularly well-annotated and cost-efficient species for modeling human disease in the therapeutic discovery pipeline. However, as a non-menstrual species with a closed tubo-ovarian junction, the mouse poses inherent challenges as a preclinical model for endometriosis research. Over the past three decades, numerous murine models of endometriosis have been described with varying degrees of fidelity in recapitulating the essential pathophysiologic features of the human disease. We conducted a search of the peer-reviewed literature to identify publications describing preclinical research using a murine model of endometriosis. Each model was reviewed according to a panel of ideal model parameters founded on the current understanding of endometriosis pathophysiology. Evaluated parameters included method of transplantation, cycle phase and type of tissue transplanted, recipient immune/ovarian status, iterative schedule of transplantation, and option for longitudinal lesion assessment. Though challenges remain, more recent models have incorporated innovative technical approaches such as in vivo fluorescence imaging and novel hormonal preparations to overcome the unique challenges posed by murine anatomy and physiology. These models offer significant advantages in lesion development and readout toward a high-fidelity mouse model for translational research in endometriosis.

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“…It is possible that iron overload and iron-mediated free radical production cause the loss of TJs proteins and degeneration of endothelial cells, and that targeting iron mediated oxidative stress provides an extended therapeutic time window against an ischemic event ( Park et al, 2011 ; Won et al, 2011 ). Excess iron accumulation induced MMPs expression ( Woo et al, 2020 ). Studies have suggested that MMPs degrade the vascular basement membrane components, resulting in disruption of the BBB ( Jin et al, 2019 ), and that excess iron accumulation will initiate the Fenton reaction to generate ROS ( Xu et al, 2020 ).…”

Section: Ferroptosis In Blood-brain Barrier Degradationmentioning

confidence: 99%

The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction

Chen

Pang

Yeo

et al. 2022

Front. Cell. Neurosci.

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The blood-brain barrier (BBB) is a selective, semi-permeable layer of endothelial cells that protects the central nervous system from harmful substances circulating in blood. It is one of the important barriers of the nervous system. BBB dysfunction is an early pathophysiological change observed in nervous system diseases. There are few treatments for BBB dysfunction, so this motivates the review. Ferroptosis is a novel cell death mode caused by iron-mediated lipid peroxidation accumulation, which has recently attracted more attention due to its possible role in nervous system disorders. Studies have shown that lipid peroxidation and iron accumulation are related to the barrier dysfunction, especially the expression of tight junction proteins. Therefore, examination of the relationship between ferroptosis and BBB dysfunction may reveal new targets for the treatment of brain diseases.

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Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype

Cited by 25 publications

References 56 publications

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction

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