Responses of mitochondrial biogenesis and function to maternal diabetes in rat embryo during the placentation period

Mitochondria are cellular organelles that have been reported to be altered in diabetes, being closely related to its associated complications. Moreover, mitochondrial biogenesis and function are essential for proper embryo development throughout the placentation period, occurring during organogenesis, when a great rate of congenital malformations have been associated with diabetic pregnancy. Thus, the aim of the current work was to investigate the effect of the diabetic environment on mitochondrial function and biogenesis during the placentation period. For this purpose, we studied the oxidative phosphorylation system (OXPHOS) enzymatic activities as well as the expression of genes involved in the coordinated regulation of both mitochondrial and nuclear genome (PGC-1alpha, NRF-1, NRF-2alpha, mtSSB, and TFAM) and mitochondrial function (COX-IV, COX-I, and beta-ATPase) in rat embryos from control and streptozotocin-induced diabetic mothers. Our results reflected that diabetic pregnancy retarded and altered embryo growth. The embryos from diabetic mothers showing normal morphology presented a reduced content of proteins regulated through the PGC-1alpha mitochondriogenic pathway on gestational day 12. This fact was accompanied by several responses that entailed the activation of OXPHOS activities on the same day and the recovery of the content of the studied proteins to control levels on day 13. As a result, the mitochondria of these embryos would reach a situation close to control on day 13 that could allow them to follow the normal mitochondriogenic schedule throughout a gestational period in which the mitochondrial differentiation process is critical. Nevertheless, malformed embryos from diabetic mothers seemed to show a lower adaptation capability, which could exacerbate their maldevelopment.     

Investigating the role of DNMT1 gene expression on myocardial ischemia reperfusion injury in rat and associated changes in mitochondria

Altered DNA methylation and mitochondrial dysfunction are the two key features of myocardial ischemia reperfusion injury (I/R), but their association with I/R remains unknown. In the present study, the relationship between DNA methyl transferase1 (DNMT1), the key methylation gene, and the mitochondrial quality control genes in rat heart during I/R was explored. We used the Langendorff rat heart model with 30 min of ischemia followed by 60 min of reperfusion and subsequent inhibition of DNMT1 with 5-azacytidine to evaluate the role of DNA methylation in I/R. Reperfusion significantly increased the expression of the DNMT1 gene, enzyme activity, and global DNA methylation levels, along with decreased mitochondrial copy, electron transport chain (ETC) activities, and ATP level. This was in agreement with the significant downregulation of 11 mitochondrial genes PGC-1α, TFAM, POLG, MFN1 and MFN2, FIS1, PARKIN, OPTN, ND1, ND4L, Cyt B and COX1 in I/R induced rat hearts. The expression pattern of the mitochondrial genes PGC-1α, TFAM, ND1 and Cyt B showed a significant negative correlation with DNMT1 expression. Rate pressure product, index of cardiac performance negatively correlated with DNMT1 expression (r = -0.8231, p = 0.0456). However, DNMT1 inhibited rat hearts via 5-azacytidine significantly improved the heart from I/R injury and reversed the I/R associated changes in the gene expression of TFAM, POLG, PGC-1α, ND1, COX1 and Cyt B, and improved the overall mtDNA copies, with a subsequent improvement in the ETC enzyme activity and ATP levels. To conclude, I/R augmented the DNMT1 activity with a subsequent increase in cardiac injury via downregulating the mitochondrial functional genes.