Balkan Journal of Medical Genetics

THE RELATIONSHIP BETWEEN TRANSCRIPT EXPRESSION LEVELS OF NUCLEAR ENCODED (TFAM, NRF1) AND MITOCHONDRIAL ENCODED (MT-CO1) GENES IN SINGLE HUMAN OOCYTES DURING OOCYTE MATURATION
Ghaffari Novin M, Allahveisi A, Noruzinia M, Farhadifar F, Yousefian E, Dehghani Fard A, Salimi M
*Corresponding Author: Dr. Azra Allahveisi, Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Pasdaran Street, Sanandaj, Iran. Tel: +98-873-664-673. Fax: +98-873-364- 674. E-mail: allavaisie@gmail.com
page: 39

DISCUSSION

Oocytes require a large supply of ATP for maturation to support critical processes such as spindle formation, chromatid separation and cell division after fertilization [24-26]. Mitochondrial number increases during oocyte maturation at a direct ratio to increase copy number of mtDNA [27-29]. For the first time, this study identified the relationship between the relative expression levels of nuclear and mitochondrial encoded genes at various stages of human oocyte maturation using single-cell qRT-PCR. This method evaluated the relative gene expression levels in single oocytes without isolating RNA. In the present study, relationship between the relative expression levels of TFAM and NRF1, and the MT-CO1 genes was significant in MI and MII stage oocytes. Therefore, it can be concluded that nuclear-mitochondrial relationships occur by active transcriptions during human oocyte maturation. No relationship was observed between mRNA expression levels of nuclear and mitochondrial encoded genes in immature oocytes (GV stage). However, contrary to the findings of the current study in GVstage oocytes, a high expression level of TFAM was observed by increasing the relative expression level of the MT-CO1 gene. In MII-stage oocytes, a significant difference was detected between the relative mRNA levels of TFAM and NRF1, and the MT-CO1 genes. This can be explained by the response of regulation mechanism to changes in energy demand associated with a large number of mtDNA copies at this stage. Previous studies have shown that a relative expression level of TFAM results in further direct mtDNA replication [18,30, 31]. Furthermore, studies have reported that NRF1 transactivates the promoters of a number of mitochondrial-linked genes such as TFAM, including genes that encode respiratory chain subunits [32]. Results showed a high expression level of the nuclear encoded TFAM gene with important mitochondrial encoded MT-CO1 gene upregulation in MI- and MII-stage oocytes, which could confirm the activation of mtDNA heavy strand promoter by TFAM, causing the relative expression of mRNA encoding mitochondrial proteins such as cytochrome oxidase subunit 1 (COX1). This causes further differentiation of mitochondria in MI and MII stages [5,33-35]. It is commonly accepted that NRF1, TFAM and MT-CO1 genes serve as markers of mitochondrial differentiation [36-38]. Moreover, it seems that the increased expression of NRF1 positively affects TFAM binding to regulatory regions of the MT-CO1 promoter; therefore, TFAM is well known as a main mitochondrial transcription factor, regulating mtDNA copy number and mtDNA transcription activity [39]. However, a relationship has been observed between the upregulated gene expression of NRF1 and TFAM, and the MT-CO1 in MII-stage oocytes, compared to GV-stage human oocytes. Similarly, previous studies have reported that TFAM reduction resulted in decreased mitochondrial COX1 expression to lower than 30.0% of the normal expression level and caused embryonic lethality [25]. Another study has revealed that delayed expression of mtDNA replication factors result in delayed mtDNA replication and reduced development of oocyte competence [27].Other studies have also demonstrated that the homozygous knockout embryos of TFAM (TFAM [‒/‒]) die due to deficiencies in impaired respiratory chain [17,23]. Therefore, it may be concluded that increase in transcription levels in oocyte mitochondria results in increase in mtDNA due to demanded ATP levels during human oocyte maturation, which are important steps in oocyte maturation [40-42]. In conclusion, the present study has supported the fact that the relationship between the relative expression level of nuclear encoded genes (TFAM, NRF1) and the mitochondrial-encoded gene (MT-CO1) is associated with human oocyte maturation and subsequently, oocyte quality. However, further investigations with appropriate methodology are required to better understand unknown aspects of this relationship. Declaration of Interest. The authors greatly appreciate the Sarem Women’s Hospital and Shahid Beheshti University of Medical Sciences, Tehran, Iran, for their support and for funding this thesis. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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