Expression patterns of mitochondrial OXPHOS components, mitofusin 1 and dynamin-related protein 1 are associated with human embryo fragmentation

Abstract

Developmental dysfunction in embryos, such as a lethal level of fragmentation, is assumed to be mitochondrial in origin. This study investigated the molecular basis of mitochondrial impairment in embryo fragmentation. Transcription patterns of factors that determine mitochondrial functionality: (i) components of the oxidative phosphorylation (OXPHOS) - complex I, cytochrome b, complex IV and ATP synthase; (ii) mitochondrial membrane potential (MMP); (iii) mitochondrial DNA (mtDNA) content and (iv) proteins involved in mitochondrial dynamics, mitofusin 1 (Mfn1) and dynamin related protein 1 (Drp1) were examined in six-cells Day 3 non-fragmented (control), low-fragmented (LF) and high-fragmented (HF) human embryos. Gene expression of mitochondria-encoded components of complex I and IV, cytochrome b and mtDNA were increased in HF embryos compared with control and LF embryos. In LF embryos, expression of these molecules was decreased compared with control and HF embryos. Both classes of fragmented embryos had decreased MMP compared with control. LF embryos had increased gene expression of Mfn1 accompanied by decreased expression of Drp1, while HF embryos had decreased Mfn1 expression but increased Drp1 expression. The study revealed that each improper transcriptional (in)activation of mitochondria-encoded components of the OXPHOS during early in vitro embryo development is associated with a decrease in MMP and with embryo fragmentation. The results also showed the importance of mitochondrial dynamics in fragmentation, at least in the extent of this process.

Mitochondria in early development: linking the microenvironment, metabolism and the epigenome

“…Perturbations in placental structure would contribute to reduced nutrient transport, thereby implicating mitochondria in regulating placental cell differentiation and fate. In addition, oocyte specific Drp1 knockout results in infertility (Udagawa et al 2014), and both decreased expression of Drp1 and increased Mfn2 mRNA levels, favouring mitochondrial fusion, have been associated with fragmented human day 3 embryos (Otasevic et al 2016), although whether this is a cause or consequence is unclear. Further, inhibition of mitochondrial fission with the specific Drp1 inhibitor Mdivi-1 reduces porcine blastocyst formation accompanied by reduced mitochondrial membrane potential and increased ROS (Yeon et al 2015), with increasing expression during early porcine cleavage stages indicative of higher quality embryos (Yang et al 2018).…”

PNA-TPP Targeting Drp1 of Lung Adenocarcinoma Cancer Stem Cells Enhance the Sensitivity to Cisplatin

“…However Drp1 activity is dependent on its activation by different post-translational modifications, including O-GlucNAcylation, SUMOylation, phosphorylation, S-nitrosylation, and glycosylation, and on the translocation from cytosol to mitochondria 21 . Evidence shows inhibition of the respiratory chain can lead to increased mitochondrial fission 22,23 . Mitochondrial DNA damage promotes mitochondrial fission, decreased mitochondrial membrane potential, reduced ATP synthesis, and increased release of cytochrome c 23 .…”

Low expression of mitofusin 1 is associated with mitochondrial dysfunction and apoptosis in porcine somatic cell nuclear transfer embryos

“…In addition, porcine SCNT blastocysts had decreased gene expression of MFN1 accompanied by increased expression of DRP1. Highly fragmented human embryos had decreased MFN1 expression, but increased DRP1 expression (Otasevic et al., 2016). In porcine embryos, tyrphostin A9 improves blastocyst development through induction of DRP1 mitochondrial fission (Ahn et al., 2017).…”