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, 21 (1), 11-22

Mitochondrial DNA Disease and Developmental Implications for Reproductive Strategies


Mitochondrial DNA Disease and Developmental Implications for Reproductive Strategies

Joerg Patrick Burgstaller et al. Mol Hum Reprod.


Mitochondrial diseases are potentially severe, incurable diseases resulting from dysfunctional mitochondria. Several important mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA), the genetic material contained within mitochondria, which is maternally inherited. Classical and modern therapeutic approaches exist to address the inheritance of mtDNA disease, but are potentially complicated by the fact that cellular mtDNA populations evolve according to poorly-understood dynamics during development and organismal lifetimes. We review these therapeutic approaches and models of mtDNA dynamics during development, and discuss the implications of recent results from these models for modern mtDNA therapies. We particularly highlight mtDNA segregation-differences in proliferative rates between different mtDNA haplotypes-as a potential and underexplored issue in such therapies. However, straightforward strategies exist to combat this and other potential therapeutic problems. In particular, we describe haplotype matching as an approach with the power to potentially ameliorate any expected issues from mtDNA incompatibility.

Keywords: development; haplotype matching; mitochondrial DNA; mtDNA segregation; preventing mtDNA disease.


Figure 1
Figure 1
The mitochondrial DNA bottleneck during development. (A) A fertilized oocyte has a given heteroplasmy (mutant load) value. During gestation, the female embryo/fetus develops primordial germ cells that develop into oocytes. The heteroplasmy in these oocytes shows high variance due to the bottleneck effect, whose proposed mechanisms are shown in (B)–(D). (B) A reduction of mitochondrial DNA (mtDNA) copy number in the primordial germ cells and consecutive reamplification during oocyte development accelerates random drift and increases variance. (C) Random partitioning of clusters of mtDNAs at each cell division during primordial germ cell development could powerfully increase heteroplasmy variance. (D) Allowing only a small random subset of mtDNAs to replicate (here two instances are depicted with circles and squares)—either a specifically selected set or through restricted random turnover—can increase heteroplasmy variance through imposing a lower effective population size.
Figure 2
Figure 2
MtDNA disease inheritance and therapeutic approaches. (A) A mother with mtDNA harboring a pathological mutation is at risk of transmitting the associated disease to her offspring. (B) Oocyte donation uses an oocyte from a third-party donor who does not carry the mtDNA mutation. (C) Preimplantation diagnosis involves sampling mutant load in cells after conception. As the mother's oocytes may exhibit a wide range of heteroplasmy levels, some concepti may inherit acceptably low mutant loads: these are retained. (D) Pronuclear transfer involves the removal of the nucleus from a third-party oocyte with unaffected mtDNA, then the transfer of two pronuclei (from the mother's egg and father's sperm) onto this healthy background. (E) Spindle transfer involves the replacement of a third-party oocyte nucleus with the chromosomal complex from the mother, prior to fertilization with the father's sperm.
Figure 3
Figure 3
Potential issues associated with mixed mtDNA populations resulting from modern therapies. (A) Incompatibilities may exist between the nuclear DNA (from mother and father) and mtDNA (from a third party), as these genomes have not necessarily co-evolved. Such incompatibilities may conceivably manifest as, for example, dysfunctional protein products or signaling pathways. (B) The mixture of two mtDNA types within a cell has been found to cause detrimental physiological effects, for unknown reasons. (C) Segregation is the proliferation of one mtDNA haplotype over another in a cellular mixture, potentially causing changes in the population fraction of one mtDNA haplotype. If one mtDNA haplotype experiences a proliferative advantage over another, it may come to dominate the cellular population over time. If some mtDNAs of this haplotype harbor a pathological mutation, this mutation may thus become amplified even if the pathological mutation itself does not affect segregation.

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