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

Redox Biol. 2022 Feb;49:102215. doi: 10.1016/j.redox.2021.102215. Epub 2021 Dec 17.


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.

Keywords: Cumulus cells-oocyte communication; Endoplasmic reticulum stress; Melatonin; Reactive oxygen species; Reproductive aging; Transzonal projections.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Cell Communication
  • Cumulus Cells
  • Female
  • Melatonin* / metabolism
  • Melatonin* / pharmacology
  • Mice
  • Oocytes


  • Antioxidants
  • Melatonin