Abstract
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.
Highlights
Mitochondria have their own DNA, which is the only DNA outside the nucleus in humans
The range of symptomatic severity associated with mitochondrial disease leads to variability in reported prevalence rates: for example, one mitochondrial pathology has quoted prevalence rates of between 1 in 300 (Manwaring et al, 2007) and 1 in 14 000 (Chinnery et al, 2000)
The majority of essential respiratory chain proteins are encoded by the nucleus, as well as many proteins required for mtDNA maintenance and replication
Summary
Mitochondrial DNA disease and developmental implications for reproductive strategies Joerg Patrick Burgstaller1,2,†*, Iain G. Another striking feature of mtDNA disease inheritance involves the observed large shifts of heteroplasmy between mother and offspring It is possible for a phenotypically healthy mother, harboring 50% mutated mtDNA, to produce both healthy and severely affected children (Larsson et al, 1992). The reason for this shift between generations is the so-called ‘bottleneck’ effect, whereby heteroplasmy levels in offspring are remarkably variable with respect to the maternal heteroplasmy, while the average heteroplasmy across many offspring is often comparable to that of the mother (Jenuth et al, 1996). The appealing catchphrases ‘like changing a laptop battery’ (referring to the replacement of dysfunctional mtDNA) and associated ‘three-parent babies’ (referring to the presence of a third-party’s mtDNA in an embryo; see below) have captured the imagination of many involved in communicating science to the general public, and several of these recently proposed therapies for mtDNA disease inheritance are currently on the verge of clinical application
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