Oxidative stress and tumor necrosis factor–α–induced alterations in metaphase II mouse oocyte spindle structure

Choi, Woo June; Banerjee, Jashoman; Falcone, Tommaso; Bena, James; Agarwal, Ashok; Sharma, Rakesh K.

doi:10.1016/j.fertnstert.2007.02.067

Cited by 126 publications

(122 citation statements)

References 76 publications

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“…Fluorescence intensity was determined using AnalysisPro software (Olympus), whereby a circle was placed over the oocyte (or COC) image, and the sum total of fluorescence within the area was determined. Oocyte spindles were scored as described previously (Choi et al, 2007), where spindle and chromosomal configurations were deemed good (score 1, 2) or abnormal (score 3, 4) based on spindle organization and the degree of chromosomal displacement from the plane of the metaphase plate.…”

Section: Lipid Droplet Staining and Immunocytochemistrymentioning

confidence: 99%

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

et al. 2015

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Over-nutrition in females causes altered fetal growth during pregnancy and permanently programs the metabolism of offspring; however, the temporal and mechanistic origins of these changes, and whether they are reversible, are unknown. We now show that, in obese female mice, cumulus-oocyte complexes exhibit endoplasmic reticulum (ER) stress, high levels of intracellular lipid, spindle abnormalities and reduced PTX3 extracellular matrix protein production. Ovulated oocytes from obese mice contain normal levels of mitochondrial (mt) DNA but have reduced mitochondrial membrane potential and high levels of autophagy compared with oocytes from lean mice. After in vitro fertilization, the oocytes of obese female mice demonstrate reduced developmental potential and form blastocysts with reduced levels of mtDNA. Blastocysts transferred to normal weight surrogates that were then analyzed at E14.5 showed that oocytes from obese mice gave rise to fetuses that were heavier than controls and had reduced liver and kidney mtDNA content per cell, indicating that maternal obesity before conception had altered the transmission of mitochondria to offspring. Treatment of the obese females with the ER stress inhibitor salubrinal or the chaperone inducer BGP-15 before ovulation increased the amount of the mitochondrial replication factors TFAM and DRP1, and mtDNA content in oocytes. Salubrinal and BGP-15 also completely restored oocyte quality, embryo development and the mtDNA content of fetal tissue to levels equivalent to those derived from lean mice. These results demonstrate that obesity before conception imparts a legacy of mitochondrial loss in offspring that is caused by ER stress and is reversible during the final stages of oocyte development and maturation.

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Section: Lipid Droplet Staining and Immunocytochemistrymentioning

confidence: 99%

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

et al. 2015

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“…Mitochondrial metabolism factors, including ATP and the pyruvate dehydrogenase complex are essential for correct oocyte spindle assembly and chromosome alignment [32][33][34]. Furthermore, examination of oocytes from diabetic mice has demonstrated that damaged mitochondria are associated with aneuploidy.…”

Section: Mtdna and Blastocyst Chromosome Statusmentioning

confidence: 99%

Altered Levels of Mitochondrial DNA Are Associated With Female Age, Aneuploidy, and Provide an Independent Measure of Embryonic Implantation Potential

Fragouli

Spath

Alfarawati

et al. 2016

Obstetrical &Amp; Gynecological Survey

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Mitochondria play a vital role in embryo development. They are the principal site of energy production and have various other critical cellular functions. Despite the importance of this organelle, little is known about the extent of variation in mitochondrial DNA (mtDNA) between individual human embryos prior to implantation. This study investigated the biological and clinical relevance of the quantity of mtDNA in 379 embryos. These were examined via a combination of microarray comparative genomic hybridisation (aCGH), quantitative PCR and next generation sequencing (NGS), providing information on chromosomal status, amount of mtDNA, and presence of mutations in the mitochondrial genome. The quantity of mtDNA was significantly higher in embryos from older women (P=0.003). Additionally, mtDNA levels were elevated in aneuploid embryos, independent of age (P=0.025). Assessment of clinical outcomes after transfer of euploid embryos to the uterus revealed that blastocysts that successfully implanted tended to contain lower mtDNA quantities than those failing to implant (P=0.007). Importantly, an mtDNA quantity threshold was established, above which implantation was never observed. Subsequently, the predictive value of this threshold was confirmed in an independent blinded prospective study, indicating that abnormal mtDNA levels are present in 30% of non-implanting euploid embryos, but are not seen in embryos forming a viable pregnancy. NGS did not reveal any increase in mutation in blastocysts with elevated mtDNA levels. The results of this study suggest that increased mtDNA may be related to elevated metabolism and are associated with reduced viability, a possibility consistent with the 'quiet embryo' hypothesis. Importantly, the findings suggest a potential role for mitochondria in female reproductive aging and the genesis of aneuploidy. Of clinical significance, we propose that mtDNA content represents a novel biomarker with potential value for in vitro fertilisation (IVF) treatment, revealing chromosomally normal blastocysts incapable of producing a viable pregnancy. Data Availability Statement: All relevant data are within the paper and its Supporting Information files.Funding: DW is supported by the NIHR Biomedical Research Centre Oxford. This study was funded by Reprogenetics UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: EF, SA and DW are employees of Reprogenetics UK. This does not alter our adherence to all PLOS Genetics policies in Author SummaryMitochondria are small membrane-enclosed structures and are found inside the cells of the body. Mitochondria actively participate in cellular life, and their main function is to generate energy which is used by the cell. For this reason mitochondria are considered as the powerhouses of cells. Unlike other cellular organelles, mitochondria contain their own DNA (mtDNA). MtDNA carries important genetic information concerning cellular metabolism and the gener...

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“…Thus, mitochondrial status has been recognized as an important factor determining mammalian oocyte quality. In particular, the factors associated with mitochondrial metabolism, such as ATP, ROS, and pyruvate dehydrogenase complex (PDH), are required for proper spindle assembly and chromosome alignment in oocyte meiosis (Choi et al., 2007; Johnson, Freeman, Gardner, & Hunt, 2007; Zhang, Wu, Lu, Guo, & Ma, 2006). …”

Section: Introductionmentioning

confidence: 99%

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

Zeng

Jiang²,

et al. 2018

Aging Cell

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SIRT4 modulates energy homeostasis in multiple cell types and tissues. However, its role in meiotic oocytes remains unknown. Here, we report that mouse oocytes overexpressing SIRT4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization. Moreover, we find that phosphorylation of Ser293‐PDHE1α mediates the effects of SIRT4 overexpression on metabolic activity and meiotic events in oocytes by performing functional rescue experiments. By chance, we discover the SIRT4 upregulation in oocytes from aged mice; and importantly, the maternal age‐associated deficient phenotypes in oocytes can be partly rescued through the knockdown of SIRT4. These findings reveal the critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and indicate that SIRT4 is an essential factor determining oocyte quality.

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Oxidative stress and tumor necrosis factor–α–induced alterations in metaphase II mouse oocyte spindle structure

Cited by 126 publications

References 76 publications

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors

Altered Levels of Mitochondrial DNA Are Associated With Female Age, Aneuploidy, and Provide an Independent Measure of Embryonic Implantation Potential

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

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