Implications Of Mitochondrial Anomalies For

Mitochondrial dysfunction is suggested as a prime cause of low oocyte and embryo quality and hence the low efficiency of human ART on a per-embryo basis. Not surprisingly, attention has been drawn to possible effects of current ARTs on mitochondrial function. The coexistence of different mitochondrial genomes in the same cell is termed mitochondrial heteroplasmy. There is evidence that heteroplasmy in some infants resulted from ''ooplasm transfer,'' a technique involving injection of ooplasm from oocytes from young women into oocytes from older women patients in an effort to improve their developmental competence (Cohen et al., 1998). In this procedure, about 10% of the ooplasm from an oocyte of a presumptively fertile donor was microinjected into a recipient oocyte from an older, infertile patient with presumptively compromised oocyte quality (Cohen et al., 1998). However, this transfer would introduce numerous cytoplasmic components into the recipient oocytes, including proteins and mRNAs as well as mitochondria and other organelles (Van Blerkom et al., 1998). It is still unknown if injection of donor mitochondria can improve the quality of oocytes and embryos derived from them, although several babies were born after this procedure. The children resulting from IVF of these oocytes were found to be carrying mitochondria from both the donor and recipient, in varying proportions in different tissues.

Heteroplasmy also results from nuclear transfer— the fusion of somatic cells with enucleated oocytes (somatic cell nuclear transfer, SCNT)—in studies on cloned sheep, cattle and monkeys. All efforts to produce identical monkeys by SCNT have failed so far to produce cloned (identical) monkeys for biomedical research, but any success in this approach will have to contend with the problem of heteroplasmy. It may be that techniques such as ooplasm transfer, nuclear transfer and other approaches involving heteroplasmy perturb the normal interchanges between nuclear and mitochondrial genomes required for proper mtDNA replication, as described above. This could account for the low success of these technologies. Nevertheless, if ooplasm transfer or the reverse procedure, ''pronuclear fusion'' (see below), is ever to gain acceptance for treatment of infertility in the older patient, it seems that their safety as well as their efficacy must first be confirmed in monkeys.

Other approaches that may cause heteroplasmy or other mitochondrial problems include the transfer of oocyte nuclei (germinal vesicles) from oocytes of older women into enucleated oocytes of younger women, in efforts to allow older women to be the genetic mothers of their babies even though ''oocyte donation'' is used. In a related technique, the nucleus of an IVF oocyte is removed and injected into an enucleated donor oocyte (''pronuclear fusion''; Zhang et al., 1999). Whether or not these techniques are effective for treatment of infertility in older patients, heteroplasmy is a concern, and possible effects of age on this condition cannot be discounted. In addition, because many of the genes required for mitochondrial function reside in the nucleus, mismatches between mitochondrial and nuclear genomes may cause problems in bioenergetics.

While mitochondria are strictly maternally inherited, paternally-derived mitochondrial are eliminated selectively during early fertilization and/or subsequent embryonic cell divisions (Sutovsky and Schatten, 2000; St. John, 2002). Nevertheless, there are some reports from human patients as well as in animals that occasionally paternal mitochondria escape the elimination process, which has sometimes resulted in severe pathologies (Cummins, 2001b). Because invasive techniques such as ICSI are becoming more prevalent in human ART, there is some concern that such techniques may increase the frequency of heteroplasmy. Paternal mitochondria can sometimes survive in abnormally fertilized embryos (St. John et al., 1997). If spermatozoa carrying mito-chondrial point mutations and deletions were introduced into an oocyte by ICSI, and mitochondria of such spermatozoa are not properly eliminated in the embryo, then there could be a possibility for inadvertent transmission of mitochondrial diseases and/or introduction of fertility problems. Because mechanisms of paternal mitochondrial elimination may differ across species, it is important that consequences of introducing sperm mtDNA mutations into embryos should be examined in an appropriate, nonhuman primate model such as the rhesus monkey using ICSI (Hewitson et al., 2002).

Recently, transmission of paternal mitochondrial DNA into nonhuman primate offspring produced by embryonic cell nuclear transfer (ECNT) was described (St. John and Schatten, 2004). This process involves not only introduction of the blastomere nucleus but also a substantial volume of blastomere cytoplasm that includes remnants of mitochondria from the fertilizing spermatozoon. Thus, there is considerable risk of aberrant mtDNA transmission in ECNT. Nonhuman primate offspring produced by ECNT actually contained three mtDNA populations, derived from maternal mtDNA from the recipient oocyte, a different maternal mtDNA from the donor blastomere, and paternal mtDNA from the fertilizing spermatozoon. This outcome represents another example of multiparental mtDNA heteroplasmy.

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