Failure of elimination of paternal mitochondrial DNA in abnormal embryos

John, Justin St; Sakkas, Denny; Dimitriadi, Konstantina; Barnes, Annette M.; Maclin, Victoria M.; Ramey, Jacques W.; Barratt, Christopher L.R.; Jonge, Christopher De

doi:10.1016/s0140-6736(99)03842-8

Cited by 95 publications

(30 citation statements)

References 3 publications

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“…Thus, another important pathway to ensure maternal mitochondrial inheritance in mice might be the elimination of sperm mtDNA before fertilization. This mechanism may imply that, when assisted reproductive technology is used, because of the deletion of natural selection of mtDNA-free sperm in the process of sperm swimming to the oviduct, the rate of embryos inheriting paternal mtDNA may be increased, which has been observed in human abnormal embryos (29).…”

Section: Sperm Mitochondria Persisted and Dispersed Unevenly In Severalmentioning

confidence: 99%

Unique insights into maternal mitochondrial inheritance in mice

Luo

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

129

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In animals, mtDNA is always transmitted through the female and this is termed “maternal inheritance.” Recently, autophagy was reported to be involved in maternal inheritance by elimination of paternal mitochondria and mtDNA in Caenorhabditis elegans ; moreover, by immunofluorescence, P62 and LC3 proteins were also found to colocalize to sperm mitochondria after fertilization in mice. Thus, it has been speculated that autophagy may be an evolutionary conserved mechanism for paternal mitochondrial elimination. However, by using two transgenic mouse strains, one bearing GFP-labeled autophagosomes and the other bearing red fluorescent protein-labeled mitochondria, we demonstrated that autophagy did not participate in the postfertilization elimination of sperm mitochondria in mice. Although P62 and LC3 proteins congregated to sperm mitochondria immediately after fertilization, sperm mitochondria were not engulfed and ultimately degraded in lysosomes until P62 and LC3 proteins disengaged from sperm mitochondria. Instead, sperm mitochondria unevenly distributed in blastomeres during cleavage and persisted in several cells until the morula stages. Furthermore, by using single sperm mtDNA PCR, we observed that most motile sperm that had reached the oviduct for fertilization had eliminated their mtDNA, leaving only vacuolar mitochondria. However, if sperm with remaining mtDNA entered the zygote, mtDNA was not eliminated and could be detected in newborn mice. Based on these results, we conclude that, in mice, maternal inheritance of mtDNA is not an active process of sperm mitochondrial and mtDNA elimination achieved through autophagy in early embryos, but may be a passive process as a result of prefertilization sperm mtDNA elimination and uneven mitochondrial distribution in embryos.

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Section: Sperm Mitochondria Persisted and Dispersed Unevenly In Severalmentioning

confidence: 99%

Unique insights into maternal mitochondrial inheritance in mice

Luo

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

129

View full text Add to dashboard Cite

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“…8 However, this occurrence must be rare on a population basis because the only other reports 39 are in abnormal embryos with arrested development. 40 We and others have previously been unable to detect significant levels of paternal mtDNA polymorphisms in placenta, even in ICSI where the normal processes governing its elimination might be disrupted. 19,41,42 In the single case report of paternally inherited mtDNA the authors identified mtDNA recombinants using PCR analysis of muscle mtDNA.…”

Section: Discussionmentioning

confidence: 87%

Mosaicism for mitochondrial DNA polymorphic variants in placenta has implications for the feasibility of prenatal diagnosis in mtDNA diseases

et al. 2006

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Women who have had a child with mitochondrial DNA (mtDNA) disease need to know the risk of recurrence, but this risk is difficult to estimate because mutant and wild-type (normal) mtDNA coexist in the same person (heteroplasmy). The possibility that a single sample may not reflect the whole organism both impedes prenatal diagnosis of most mtDNA diseases, and suggests radical alternative strategies such as nuclear transfer. We used naturally occurring mtDNA variants to investigate mtDNA segregation in placenta. Using large samples of control placenta, we demonstrated that the level of polymorphic heteroplasmic mtDNA variants is very similar in mother, cord blood and placenta. However, where placental samples were very small (o10 mg) there was clear evidence of variation in the distribution of mtDNA polymorphic variants. We present the first evidence for variation in mutant load, that is, mosaicism for mtDNA polymorphic variants in placenta. This suggests that mtDNA mutants may segregate in placenta and that a single chorionic villous sample (CVS) may be unrepresentative of the whole placenta. Duplicates may be necessary where CVS are small. However, the close correlation of mutant load in maternal, fetal blood and placental mtDNA suggests that the average load in placenta does reflect the load of mutant mtDNA in the baby. Provided that segregation of neutral and pathogenic mtDNA mutants is similar in utero, our results are generally encouraging for developing prenatal diagnosis for mtDNA diseases. Identifying mtDNA segregation in human placenta suggests studies of relevance to placental evolution and to developmental biology.

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“…En conséquence, l'augmentation du taux d'ADNmt dans le sperme des patients infertiles, soulève le problème des risques inhérents au déve-loppement des techniques d'Assistance médicale à la procréa-tion (AMP). En effet, bien que les premières études sur la transmission de l'ADNmt après ICSI suggèrent que l'embryon humain élimine l'ADNmt du spermatozoïde injecté [67], une étude a montré que la persistance de l'ADNmt paternel serait possible en cas d'utilisation de gamètes de mauvaise qualité [27]. Ainsi, il ne peut pas être exclu que l'injection de spermatozoïdes contenant un taux important d'ADNmt puisse rendre possible la transmission paternelle de l'ADNmt sans que l'on en connaisse les conséquences à plus ou moins long terme.…”

Section: Resultsunclassified

“…Seules quelques exceptions laissent entrevoir la possibilité d'une transmission de l'ADNmt paternel. Outre, le cas de certaines espèces comme la moule marine Mytilus [26], il a été montré que l'ADNmt paternel pouvait persister dans des embryons humains anormaux [27] et même être exceptionnellement retrouvé à l'âge adulte dans le cadre de cytopathies mitochondriales [28,29]. La diminution drastique du nombre de copies d'ADNmt au cours de la spermatogenèse, l'absence de réplica-tion de l'ADNmt au sein de l'ovocyte et l'élimination spéci-fique des mitochondries paternelles dans l'ovocyte sont autant de mécanismes avancés pour rendre compte de la nontransmission de l'ADNmt paternel [30].…”

Section: Transmission Du Génome Mitochondrialunclassified