Abstract
In various animal species, the main cause of pregnancy loss in conceptuses obtained by somatic cell nuclear transfer (SCNT) are placental abnormalities. Most abnormalities described in SCNT pregnancies (such as placentomegaly, reduced vascularisation, hypoplasia of trophoblastic epithelium) suggest that placental cell degeneration may be triggered by mitochondrial failure. We hypothesized that placental abnormalities of clones obtained by SCNT are related to mitochondrial dysfunction. To test this, early SCNT and control (CTR, from pregnancies obtained by in vitro fertilization) placentae were collected from pregnant ewes (at day 20 and 22 of gestation) and subjected to morphological, mRNA and protein analysis. Here, we demonstrated swollen and fragmented mitochondria and low expression of mitofusin 2 (Mfn2), the protein which plays a crucial role in mitochondrial functionality, in SCNT early placentae. Furthermore, reduced expression of the Bcnl3L/Nix protein, which plays a crucial role in selective elimination of damaged mitochondria, was observed and reflected by the accumulation of numerous damaged mitochondria in SCNT placental cells. Likely, this accumulation of damaged organelles led to uncontrolled apoptosis in SCNT placentae, as demonstrated by the high number of apoptotic bodies, fragmented cytoplasm, condensed chromatin, lack of integrity of the nuclear membrane and the perturbed mRNA expression of apoptotic genes (BCL2 and BAX). In conclusion, our data indicate that deregulated expression of Mfn2 and Bcnl3L is responsible for placental abnormalities in SCNT conceptuses. Our results suggest that some nuclear genes, that are involved in the regulation of mitochondrial function, do not work well and consequently this influence the function of mitochondria.
Highlights
Somatic Cell Nuclear Transfer (SCNT) allows the asexual reproduction of an individual by transplanting a somatic cell into an enucleated oocyte
Our previous work suggested that the abnormalities described for somatic cell nuclear transfer (SCNT) placentae might have features in common with mitochondrial dysfunction [9, 12]
We report that deregulated expression of mitochondrial proteins (Mfn2 and Bcnl3L) cause placental abnormalities and may negatively affect SCNT embryo development
Summary
Somatic Cell Nuclear Transfer (SCNT) allows the asexual reproduction of an individual by transplanting a somatic cell into an enucleated oocyte. SCNT has tremendous potential for therapeutic cloning/regenerative medicine [1], the rescue of endangered species [2], and production of transgenic animals with high efficiency [3]. Cloning efficiency is currently very low, and even though there are differences between species, only 2–5% of offspring are commonly delivered [4]. SCNT is associated with high rates of fetal and perinatal losses and abnormal offspring [5]. The most common placental abnormalities described in clones are placentomegaly [10], reduced vascularisation, hypoplasia of trophoblastic epithelium [7], lower numbers of binuclear cells [9,11], and altered basement membrane [12]. Investigations into mitochondria in SCNT are limited to the mtDNA hetero/homoplasmy in the tissue of cloned offspring; no data are available for the role of mitochondria dysfunction in the developmental failure of clones
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