Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells. Hum Reprod Update

Clinical Sciences Research Institute, Warwick Medical School, CSB-University Hospital, Coventry, UK.
Human Reproduction Update (Impact Factor: 10.17). 03/2010; 16(5):488-509. DOI: 10.1093/humupd/dmq002
Source: PubMed


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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    • "mtDNA replication proceeds and increases with cell differentiation. Therefore, mitochondria become mature and capable of oxidative metabolism only during and after the blastocyst stage (Facucho-Oliveira et al., 2007; reviewed by St John et al., 2010). A series of cellular changes and diseases are closely related to mutations in the number of mtDNA copies (King and Attardi, 1996; Scarpulla, 2008). "
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    ABSTRACT: Large number of cellular changes and diseases are related to mutations in the mitochondrial DNA copy number. Cell culture in the presence of ethidium bromide is a known way of depleting mitochondrial DNA and is a useful model for studying such conditions. Interestingly, the morphology of these depleted cells resembles that of pluripotent cells, as they present larger and fragmented mitochondria with poorly developed cristae. Herein, we aimed to study the mechanisms responsible for the control of mitochondrial DNA replication during mitochondrial DNA depletion mediated by ethidium bromide and during the in vitro induction of cellular pluripotency with exogenous transcription factor expression in a bovine model. This article reports the generation of a bovine Rho0 mesenchymal cell line and describes the analysis of mitochondrial DNA copy number in a time-dependent manner. The expression of apoptosis and mitochondrial-related genes in the cells during mitochondrial DNA repletion were also analyzed. The dynamics of mitochondrial DNA during both the depletion process and in vitro reprogramming are discussed. It was possible to obtain bovine mesenchymal cells almost completely depleted of their mitochondrial DNA content (over 90%). However, the production of induced pluripotent stem cells from the transduction of both control and Rho0 bovine mesenchymal cells with human reprograming factors was not successful.
    No preview · Article · Nov 2015 · Genetics and molecular research: GMR
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    • "During the different phases of oogenesis and embryogenesis, a great quantity of energy is requested to support oocyte maturation, fertilization and embryo development, which is provided by the thousands of mitochondria accumulated during oogenesis. These maternally inherited cytoplasmic organelles are the site of production of energy through the synthesis of adenosine triphosphate (ATP) molecules, by converting pyruvate to carbon dioxide and water via the Krebs cycle and oxidative phosphorylation (reviewed in St John et al., 2010). "
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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.
    Full-text · Article · Oct 2014 · Molecular Human Reproduction
    • "Interestingly, a study performed in primate adult ASC reported that low-passage cell cultures, containing a high proportion of undifferentiated stem cells, show significant perinuclear clustering of mitochondria when compared to late-passage cells[49]. Additionally, a study conducted on embryonic stem cell undergoing differentiation has shown high level of mitochondrial activity, which may be due to mitochondrial DNA replication[50]. We can speculate that the degree of mitochondrial activity in adult stem cells may also be strongly dependent upon the target lineages into which these cells differentiate. "
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    ABSTRACT: Adult mesenchymal stem cells, specifically adipose-derived stem cells have self-renewal and multiple differentiation potentials and have shown to be the ideal candidate for therapeutic applications in regenerative medicine, particularly in peripheral nerve regeneration. Adipose-derived stem cells are easily harvested, although they may show the effects of aging, hence their potential in nerve repair may be limited by cellular senescence or donor age. Cellular senescence is a complex process whereby stem cells grow old as consequence of intrinsic events (e.g., DNA damage) or environmental cues (e.g., stressful stimuli or diseases), which determine a permanent growth arrest. Several mechanisms are implicated in stem cell senescence, although no one is exclusive of the others. In this review we report some of the most important factors modulating the senescence process, which can influence adipose-derived stem cell morphology and function, and compromise their clinical application for peripheral nerve regenerative cell therapy.
    No preview · Article · Sep 2014 · Neural Regeneration Research
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