Melatonin improves the quality of maternally aged oocytes by maintaining intercellular communication and antioxidant metabolite supply

Abstract

In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it mediates the transfer of metabolic support molecules. However, aging-mediated dysregulation in communication between the oocytes and granulosa cells affects the oocyte quality. In the present study, we examined the defected germline-soma communication and reduced mRNA levels encoding key structural components of transzonal projections (TZPs) in maternally aged oocytes. Oral administration of melatonin to aged mice substantially increased TZPs and maintained the cumulus cells-oocyte communication, which played a central role in the production of adequate oocyte ATP levels and reducing the accumulation of reactive oxygen species (ROS), apoptosis, DNA damage, endoplasmic reticulum (ER) stress and spindle/chromosomal defects. This beneficial effect of melatonin was inhibited by carbenoxolone (CBX), a gap junctional uncoupler, which disrupts bidirectional communications between oocyte and somatic cells. Simultaneously, melatonin significantly increased the mRNA and protein levels corresponding to genes associated with TZPs and prevented TZP retraction in in vitro-cultured cumulus-oocyte complex (COCs). Furthermore, we infused melatonin and CBX into the COCs in vitro culture system and monitored the levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in cumulus cells and oocytes. Notably, COCs treated with melatonin demonstrated improved NADPH and GSH levels. Of note, CBX was capable of reducing NADPH and GSH levels, aggravated the ROS accumulation and ER stress. Collectively, our data demonstrate the role of melatonin in preventing age-associated germline-soma communication defects, aiding the relay of antioxidant metabolic molecules for the maintenance of oocyte quality from cumulus cells, which have important potential for improving deficient phenotypes of maternally aged oocytes and the treatment of woman infertility.

Effects of Melatonin on the Transcriptome of Human Granulosa Cells, Fertilization and Blastocyst Formation

“…Therefore, it is unclear whether these in vitro effects of melatonin are also true in GCs within the follicles. While melatonin administration in vivo has previously been shown to affect gene expressions in mouse GCs, such as Sirt1 and Myo10 [ 28 , 29 ], the present study is the first to show it also affects the transcriptome in human GCs. Our analysis revealed that melatonin administration altered the transcriptome in human GCs of patients with poor ART outcomes into that of patients with good ART outcomes, indicating that melatonin improves ART outcomes by altering the expressions of a number of genes in human GCs.…”

Exogenous Melatonin Directly and Indirectly Influences Sheep Oocytes

“…One aspect that needs to be considered in this area is how MT is enriched from the blood and how it can pass through the blood ovum barrier. It is involved in the cell crosstalk of oocytes and cumulus cells ( 71 ). If MT is secreted by granulosa cells or cumulus cells, this suggests that we should study the effect of it on oocytes from the aspects of endogenous MT autocrine and paracrine functions.…”

“…If MT is secreted by granulosa cells or cumulus cells, this suggests that we should study the effect of it on oocytes from the aspects of endogenous MT autocrine and paracrine functions. MT can inhibit oocyte apoptosis ( 71 ). Regarding studies on oocyte apoptosis caused by injury ( 72 , 73 ), we suggest that this should be confirmed by pyroptosis.…”

Redox signaling at the crossroads of human health and disease

“… 348 Under this condition, an imbalanced redox status prompts ROS‐mediated pathophysiological redox signaling including the classical Nrf2, NF‐κB, and AMPK signaling pathways. 349 , 350 , 351 From the perspective of a single cell, redox imbalance in aging accounts for mitochondrial dysfunction, 352 protein misfolding and aggregate formation, 353 abnormal cell membranes and intercellular communication, 354 and cell death and senescence 355 by aberrantly modulating multiple signaling pathways, among which mitochondrial dysfunction is strongly associated with aging and aging‐related disorders through ROS control. For example, aging‐induced ROS increased DNA damage and activated DNA‐dependent protein kinase, phosphorylating and counteracting the chaperone function of HSP90‐α for clients that aggravated mitochondrial dysfunction.…”