Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity

Mihalas, Bettina P.; Bromfield, Elizabeth G.; Sutherland, Jessie M.; Iuliis, Geoffry N. De; McLaughlin, Eileen A.; Aitken, R. John; Nixon, Brett

doi:10.1074/jbc.ra118.005751

Cited by 41 publications

(25 citation statements)

References 122 publications

(132 reference statements)

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“…To demonstrate if melatonin regulated CME by its antioxidative mechanism, H 2 O 2 was supplemented in the IVM culture solution at a final concentration of 35 μM, as referenced from murine oocytes . GV‐stage oocytes were divided into three IVM groups—the control group, 35 μM H 2 O 2 alone (the H group), or 35 μM H 2 O 2 along with 10 −11 M melatonin (the H + M group).…”

Section: Methodsmentioning

confidence: 99%

Melatonin promotes human oocyte maturation and early embryo development by enhancing clathrin‐mediated endocytosis

Liu

et al. 2019

Journal of Pineal Research

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Embryo development potential and reproductive clinical outcomes are all deeply rooted in oocyte maturation. Melatonin has been reported to promote oocyte maturation as an antioxidant in nonprimate species. Its antioxidative functions also help reduce plasma membrane rigidity, which facilitates clathrin‐mediated endocytosis (CME). Whether melatonin has effects on human oocyte maturation by regulating CME is worthy of exploration. In this study, we found that the optimal melatonin concentration for human oocyte maturation was 10−11 M, and the maturation rate of this group was 71.9% (P = .03). The metaphase II (MII) stage oocytes obtained by in vitro maturation with 10−11 M melatonin had a significantly higher fertilization rate (81.4% vs 61.4%, respectively, P = .017) and blastocyst rate (32.2% vs 15.8%, respectively, P = .039) compared to controls. During maturation, antioxidative melatonin greatly enhanced CME and decreased intra‐oocyte cAMP level. The former was evidenced by the increasing numbers of coated pits and vesicles, and the upregulated expression of two major CME markers—clathrin and adaptor protein‐2 (AP2). CME inhibitor dynasore increased intra‐oocyte cAMP level and blocked oocyte maturation, and melatonin could partly rescue oocyte maturation and significantly elevate the expression of clathrin and AP2 in the presence of dynasore. Therefore, we conclude that melatonin could promote human oocyte maturation and early embryo development through enhancing CME.

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Section: Methodsmentioning

confidence: 99%

Melatonin promotes human oocyte maturation and early embryo development by enhancing clathrin‐mediated endocytosis

Liu

et al. 2019

Journal of Pineal Research

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“…Although the precise mechanistic basis behind age-related decline in oocyte quality is poorly understood, it is a well-recognized fact that oxidative stress is a main contributor to this phenomenon [77]. It is also well-established that oocytes with declined quality are likely to have a significantly reduced competence for early embryonic development.…”

Section: Se Effect On In Vitro Embryo Developmental Potentialmentioning

confidence: 99%

“…Nevertheless, it is now well understandable that the decline in oocyte quality and competence is multifactorial and a wholistic and generalized perspective covering all developmental stages of oocytes is needed to fully elucidate the underlaying aging mechanisms [3]. It is also argued that antioxidant intervention aimed at alleviating the oxidative insult in oocytes should be adopted in vivo to mitigate the cumulative age-associated oxidative stress rather than as a late-stage therapy to alleviate the cellular perturbations in oocytes once such stressful manifestations have been established [77].…”

Section: Se Effect On In Vitro Embryo Developmental Potentialmentioning

confidence: 99%

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

et al. 2019

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Female reproductive (ovarian) aging is distinctively characterized by a markedly reduced reproductive function due to a remarkable decline in quality and quantity of follicles and oocytes. Selenium (Se) has been implicated in playing many important biological roles in male fertility and reproduction; however, its potential roles in female reproduction, particularly in aging subjects, remain poorly elucidated. Therefore, in the current study we used a murine model of female reproductive aging and elucidated how different Se-levels might affect the reproductive efficiency in aging females. Our results showed that at the end of an 8-week dietary trial, whole-blood Se concentration and blood total antioxidant capacity (TAOC) were significantly reduced in Se-deficient (0.08 mg Se/kg; Se-D) mice, whereas both of these biomarkers were significantly higher in inorganic (0.33 mg/kg; ISe-S) and organic (0.33 mg/kg; OSe-S) Se-supplemented groups. Similarly, compared to the Se-D group, Se supplementation significantly ameliorated the maintenance of follicles and reduced the rate of apoptosis in ovaries. Meanwhile, the rate of in vitro-produced embryos resulting from germinal vesicle (GV) oocytes was also significantly improved in Se-supplemented (ISe-S and OSe-S) groups compared to the Se-D mice, in which none of the embryos developed to the hatched blastocyst stage. RT-qPCR results revealed that mRNA expression of Gpx1, Gpx3, Gpx4, Selenof, p21, and Bcl-2 genes in ovaries of aging mice was differentially modulated by dietary Se levels. A considerably higher mRNA expression of Gpx1, Gpx3, Gpx4, and Selenof was observed in Se-supplemented groups compared to the Se-D group. Similarly, mRNA expression of Bcl-2 and p21 was significantly lower in Se-supplemented groups. Immunohistochemical assay also revealed a significantly higher expression of GPX4 in Se-supplemented mice. Our results reasonably indicate that Se deficiency (or marginal levels) can negatively impact the fertility and reproduction in females, particularly those of an advancing age, and that the Se supplementation (inorganic and organic) can substantiate ovarian function and overall reproductive efficiency in aging females.

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“…The ensuing peroxidation reactions generate appreciable levels of highly reactive short chain carbonyl compounds. Among the most abundant and cytotoxic of these secondary oxidation products is 4-hydroxynonenal (4HNE) (Petersen and Doorn, 2004); an aldehyde that has become a major focus in the field due to the pathophysiological impact it exerts on both male (Aitken et al, 2012;Baker et al, 2015;Bromfield et al, 2017b) and female germ cells (Lord et al, 2015;Mihalas et al, 2017Mihalas et al, , 2018. Under normal physiological conditions, aldehyde-metabolizing enzymes function to detoxify 4HNE, and to abrogate its cellular accumulation, thus limiting its ability to propagate oxidative cellular damage (Hauck and Bernlohr, 2016).…”

Section: Introductionmentioning

confidence: 99%

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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Oxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly reactive lipid aldehyde elicits a spectrum of cytotoxic lesions owing to its propensity to form stable adducts with biomolecules. Notably however, not all elements of the sperm proteome appear to display an equivalent vulnerability to 4HNE modification, with only a small number of putative targets having been identified to date. Here, we validate one such target of 4HNE adduction, A-Kinase Anchor Protein 4 (AKAP4); a major component of the sperm fibrous sheath responsible for regulating the signal transduction and metabolic pathways that support sperm motility and capacitation. Our data confirm that both the precursor (proAKAP4), and mature form of AKAP4, are conserved targets of 4HNE adduction in primary cultures of post-meiotic male germ cells (round spermatids) and in mature mouse and human spermatozoa. We further demonstrate that 4HNE treatment of round spermatids and mature spermatozoa results in a substantial reduction in the levels of both proAKAP4 and AKAP4 proteins. This response proved refractory to pharmacological inhibition of proteolysis, but coincided with an apparent increase in the degree of protein aggregation. Further, we demonstrate that 4HNE-mediated protein degradation and/or aggregation culminates in reduced levels of capacitation-associated phosphorylation in mature human spermatozoa, possibly due to dysregulation of the signaling framework assembled around the AKAP4 scaffold. Together, these findings suggest that AKAP4 plays an important role in the pathophysiological responses to 4HNE, thus strengthening the importance of AKAP4 as a biomarker of sperm quality, and providing the impetus for the design of an efficacious antioxidant-based intervention strategy to alleviate sperm dysfunction.

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Oxidative damage in naturally aged mouse oocytes is exacerbated by dysregulation of proteasomal activity

Cited by 41 publications

References 122 publications

Melatonin promotes human oocyte maturation and early embryo development by enhancing clathrin‐mediated endocytosis

Melatonin promotes human oocyte maturation and early embryo development by enhancing clathrin‐mediated endocytosis

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

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