Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells
ABSTRACT Mitochondrial DNA (mtDNA) encodes key proteins associated with the process of oxidative phosphorylation. Defects to mtDNA cause severe disease phenotypes that can affect offspring survival. The aim of this review is to identify how mtDNA is replicated as it transits from the fertilized oocyte into the preimplantation embryo, the fetus and offspring. Approaches for deriving offspring and embryonic stem cells (ESCs) are analysed to determine their potential application for the prevention and treatment of mtDNA disease.
The scientific literature was investigated to determine how mtDNA is transmitted, replicated and segregated during pluripotency, differentiation and development. It was also probed to understand how the mtDNA nucleoid is regulated in somatic cells.
mtDNA replication is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. At the blastocyst stage, the onset of mtDNA replication is specific to the trophectodermal cells. The inner cell mass cells restrict mtDNA replication until they receive the key signals to commit to specific cell types. However, it is necessary to determine whether somatic cells reprogrammed through somatic cell nuclear transfer, induced pluripotency or fusion to an ESC are able to regulate mtDNA replication so that they can be used for patient-specific cell therapies and to model disease.
Prevention of the transmission of mtDNA disease from one generation to the next is still restricted by our lack of understanding as to how to ensure that a donor karyoplast transferred to an enucleated oocyte is free of accompanying mutant mtDNA. Techniques still need to be developed if stem cells are to be used to treat mtDNA disease in those patients already suffering from the phenotype.
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ABSTRACT: To investigate the mitochondrial DNA (mtDNA) segregation in human oocytes, the level of heteroplasmy in the three products of meioses, polar bodies (PBs) and corresponding oocytes, was assessed by studying the hypervariable region I (HVRI) of the D-loop region. The DNA from 122 PBs and 51 oocyte from 16 patients was amplified by whole genome amplification (WGA). An aliquot of the WGA product was used to assess aneuploidy, and another aliquot to study mtDNA. The HVRI was amplified and sequenced with an efficiency of 75.4% and 63%, respectively, in PBs, and of 100% in oocytes. The comparison with the mtDNA sequences from blood of the individual donors showed full correspondence of polymorphisms with the matching oocytes, whilst in PBs the degree of concordance dropped to 89.6%. Haplogroups were inferred for all 16 patients. Of the 89 diagnosed PBs from the 13 patients belonging to macrohaplogroup R, 23 were euploid and 66 aneuploid. The incidence of total anomalies was significantly lower in haplogroup H (6.5%) when compared with haplogroups J and T (17.6 and 13.4% respectively; p<0.001). In haplogroup J, hypoaneuploidy occurred more frequently than hyperaneuploidy). In the 3 patients belonging to haplogroup N*, 81% of PBs were aneuploid with similar rates of chromosome hypoaneuploidy and hyperaneuploidy. The presence of mtDNA base changes confined to PBs could reflect a selection mechanism against severe mtDNA mutations, while permitting a high evolution rate that could result in bioenergetic diversity. The different susceptibility to aneuploidy by some haplogroups strongly supports this hypothesis.Molecular Human Reproduction 10/2014; 70(4). DOI:10.1093/molehr/gau092 · 3.48 Impact Factor
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ABSTRACT: The mitochondrion is the major energy provider to power sperm motility. In mammals, aside from the nuclear genome, mitochondrial DNA (mtDNA) also contributes to oxidative phosphorylation to impact production of ATP by coding 13 polypeptides. However, the role of sperm mitochondria in fertilization and its final fate after fertilization are still controversial. The viewpoints that sperm bearing more mtDNA will have a better fertilizing capability and that sperm mtDNA is actively eliminated during early embryogenesis are widely accepted. However, this may be not true for several mammalian species, including mice and humans. Here, we review the sperm mitochondria and their mtDNA in sperm functions, and the mechanisms of maternal mitochondrial inheritance in mammals.Journal of Genetics and Genomics 11/2013; 40(11):549-56. DOI:10.1016/j.jgg.2013.08.004 · 2.92 Impact Factor
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ABSTRACT: Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilization ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondrial-derived ATP is not crucial for sperm motility, and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as intracellular Ca2+ stores, although their role in signalling is still unclear.Reproduction 07/2013; DOI:10.1530/REP-13-0178