Abstract
Polycystic ovarian syndrome (PCOS) is associated with hyperhomocysteinemia and polycystic ovaries (PCO) usually produce oocytes of poor quality. However, the intracellular mechanism linking hyperhomocysteinemia and oocyte quality remains elusive. In this study, the quality of the oocytes isolated from healthy and polycystic gilt ovaries was evaluated in vitro in association with one-carbon metabolism, mitochondrial DNA (mtDNA) methylation, and mitochondrial function. PCO oocytes demonstrated impaired polar body extrusion, and significantly decreased cleavage and blastocyst rates. The mitochondrial distribution was disrupted in PCO oocytes, together with decreased mitochondrial membrane potential and deformed mitochondrial structure. The mtDNA copy number and the expression of mtDNA-encoded genes were significantly lower in PCO oocytes. Homocysteine concentration in follicular fluid was significantly higher in PCO group, which was associated with significantly up-regulated one-carbon metabolic enzymes betaine homocysteine methyltransferase (BHMT), glycine N-methyltransferase (GNMT) and the DNA methyltransferase DNMT1. Moreover, mtDNA sequences coding for 12S, 16S rRNA and ND4, as well as the D-loop region were significantly hypermethylated in PCO oocytes. These results indicate that an abnormal activation of one-carbon metabolism and hypermethylation of mtDNA may contribute, largely, to the mitochondrial malfunction and decreased quality of PCO-derived oocytes in gilts.
Highlights
Mammalian mitochondrial DNA is approximately 16 kb in size, encoding 13 proteins which are subunits of the OXPHOS complexes, 22 transfer RNAs, and 2 ribosomal RNAs25
No significant difference was observed between two groups in the cleavage rate after parthenogenetic activation at the 2-cell stage, yet the cleavage rate at the 4-cell stage (P < 0.05) and the blastocyst rate (P < 0.01) were significantly lower in polycystic ovaries (PCO) group compared with the control group
The present study provides the first evidence that the abnormal activation of one-carbon metabolism and the hypermethylation of mitochondrial DNA (mtDNA) are associated with mitochondrial malfunction and the poor quality of oocytes derived from polycystic ovaries of gilts
Summary
Mammalian mitochondrial DNA (mtDNA) is approximately 16 kb in size, encoding 13 proteins which are subunits of the OXPHOS complexes, 22 transfer RNAs, and 2 ribosomal RNAs25. Similar to nuclear DNA, mtDNA is subjected to epigenetic modifications that influence mitochondrial gene expression, biogenesis and function[26,27]. MtDNA methylation has received increasing attention as changes in mtDNA methylation are found to be associated with mitochondria dysfunction and thereby the pathogenesis of many metabolic diseases[28,29]. Methylation of nuclear DNA is closely related to one-carbon metabolism[37,38,39,40], yet no evidences are available linking one-carbon metabolism with mtDNA methylation and mitochondrial functions. We use polycystic ovaries of gilts as model to investigate the possible association between one-carbon metabolic pathway, mtDNA methylation, mitochondrial function and oocyte quality. The findings will help to understand the underlying causes of poor oocyte quality in PCOS patients
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