Mitochondrial Replacement, Evolution, and the Clinic

Reinhardt, Klaus; Dowling, Damian K.; Morrow, Edward H.

doi:10.1126/science.1237146

Cited by 148 publications

(148 citation statements)

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“…B 369: 20130443 exempt from the processes shaping mitonuclear coevolution and the ensuing effects. For instance, variance in mitonuclear compatibility could arise between divergent mitochondrial haplogroups and associated nucleotypes, which might predispose themselves to multifaceted and complex disease phenotypes [109]. It is well established that mitochondria are central to a multitude of disease phenotypes, yet, in many instances, straightforward links between mtDNA mutation and disease expression do not exist, and it remains largely unknown how this influence is exerted.…”

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Wolff

Ladoukakis

Enrı́quez

et al. 2014

Phil. Trans. R. Soc. B

Self Cite

196

214

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Fundamental biological processes hinge on coordinated interactions between genes spanning two obligate genomes—mitochondrial and nuclear. These interactions are key to complex life, and allelic variation that accumulates and persists at the loci embroiled in such intergenomic interactions should therefore be subjected to intense selection to maintain integrity of the mitochondrial electron transport system. Here, we compile evidence that suggests that mitochondrial–nuclear (mitonuclear) allelic interactions are evolutionarily significant modulators of the expression of key health-related and life-history phenotypes, across several biological scales—within species (intra- and interpopulational) and between species. We then introduce a new frontier for the study of mitonuclear interactions—those that occur within individuals, and are fuelled by the mtDNA heteroplasmy and the existence of nuclear-encoded mitochondrial gene duplicates and isoforms. Empirical evidence supports the idea of high-resolution tissue- and environment-specific modulation of intraindividual mitonuclear interactions. Predicting the penetrance, severity and expression patterns of mtDNA-induced mitochondrial diseases remains a conundrum. We contend that a deeper understanding of the dynamics and ramifications of mitonuclear interactions, across all biological levels, will provide key insights that tangibly advance our understanding, not only of core evolutionary processes, but also of the complex genetics underlying human mitochondrial disease.

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Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Wolff

Ladoukakis

Enrı́quez

et al. 2014

Phil. Trans. R. Soc. B

Self Cite

196

214

View full text Add to dashboard Cite

show abstract

“…Furthermore, different mtDNA variants have recently been implicated in the penetrance or severity of a range of late-onset human diseases that were previously thought to be unrelated to mitochondrial function, from schizophrenia, to multiple sclerosis and Parkinson's disease (Hudson et al 2014). Thus, it is becoming apparent that the genetic variation that accumulates within the mtDNA sequences of natural populations of metazoans does play an important role in determining health outcomes, by contributing to metabolic health, development trajectories, lifespan and the risk of disease progression (Wallace 2005, Dowling et al 2008, Reinhardt et al 2013, Dowling 2014.…”

Section: The Mitochondrial Genotype-phenotype Linkagementioning

confidence: 99%

Maternal inheritance of mitochondria: implications for male fertility?

Vaught

Dowling

2018

Reproduction

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Evolutionary theory predicts maternal inheritance of the mitochondria will lead to the accumulation of mutations in the mitochondrial DNA (mtDNA) that impair male fertility, but leave females unaffected. The hypothesis has been referred to as 'Mother's Curse'. There are many examples of mtDNA mutations or haplotypes, in humans and other metazoans, associated with decreases in sperm performance, but seemingly few reports of associations involving female reproductive traits; an observation that has been used to support the Mother's Curse hypothesis. However, it is unclear whether apparent signatures of male bias in mitochondrial genetic effects on fertility reflect an underlying biological bias or a technical bias resulting from a lack of studies to have screened for female effects. Here, we conduct a systematic literature search of studies reporting mitochondrial genetic effects on fertility-related traits in gonochoristic metazoans (animals with two distinct sexes). Studies of female reproductive outcomes were sparse, reflecting a large technical sex bias across the literature. We were only able to make a valid assessment of sex specificity of mitochondrial genetic effects in 30% of cases. However, in most of these cases, the effects were male biased, including examples of male bias associated with mtDNA mutations in humans. These results are therefore consistent with the hypothesis that maternal inheritance has enriched mtDNA sequences with mutations that specifically impair male fertility. However, future research that redresses the technical imbalance in studies conducted per sex will be key to enabling researchers to fully assess the wider implications of the Mother's Curse hypothesis to male reproductive biology.Reproduction (2018) 155 R159-R168

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“…The mitochondrial replacement should be practiced only in cases in which molecular causes are well-characterized. Second, the procedure of human mitochondrial replacement might impact negatively on highly coordinated mitochondrial-nuclear allelic interactions that have become optimized over evolutionary time (Reinhardt et al, 2013). This scientific issue suggests a The HFEA, in a brief press release, insufficiently rebutted these arguments put forward by Reinhardt et al (2013), declaring that it would be necessary to monitor the children during their lifetime and ensuring the traceability of gametes and embryos (HFEA, 2013a).…”

Section: Safety Of Mitochondrial Replacementmentioning

confidence: 99%

“…Moreover, there are biomedical reasons to question the procedure (Koopman et al, 2012;Reinhardt et al, 2013;St John and Campbell, 2010). Furthermore, a criticism was made to dissect biological implications of tri-parental origin of offspring from mitochondrial replacement (Cohen and Alikani, 2013).…”

Section: Introductionmentioning

confidence: 99%

Potential impact of human mitochondrial replacement on global policy regarding germline gene modification

Ishii

2014

Reproductive BioMedicine Online

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Mitochondrial Replacement, Evolution, and the Clinic

Abstract: Mitochondrial replacement therapy might bear health risks, especially for males.

Cited by 148 publications

References 10 publications

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Maternal inheritance of mitochondria: implications for male fertility?

Potential impact of human mitochondrial replacement on global policy regarding germline gene modification

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