Assisted reproductive technologies to prevent human mitochondrial disease transmission

Greenfield, Andy; Braude, Peter; Flinter, Frances; Lovell-Badge, Robin; Ogilvie, Caroline Mackie; Perry, Anthony C.F.

doi:10.1038/nbt.3997

Cited by 90 publications

(60 citation statements)

References 96 publications

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“…Apoptosis, known as programmed cell death, occurs in both physiological and pathological conditions (Shimada et al, ). Mitochondrial functions are strongly associated with cell proliferation and apoptosis (Greenfield et al, ). The Bcl‐2 protein family regulates mitochondrial‐mediated apoptosis by inducing loss of the MMP, followed by the release of cytochrome c into the cytosol (Pena‐Blanco & Garcia‐Saez, ).…”

Section: Discussionmentioning

confidence: 99%

1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways

Fan

Wang

et al. 2018

Journal Cellular Physiology

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1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one (EB30) is a diarylheptanoid‐like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC‐7901, and MCF‐7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI‐H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p‐ERK1/2 and p‐P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway.

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Section: Discussionmentioning

confidence: 99%

1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways

Fan

Wang

et al. 2018

Journal Cellular Physiology

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“…Two techniques have been developed to avoid transmission of mutations in mtDNA [ 79 , 80 ]. The first has been developed in the U.K., where the treatment is now licensed for use in humans, and is based on the pronuclear transfer from an affected donor into an enucleated healthy embryo shortly after completion of meiosis [ 81 ].…”

Section: Pre-implantation Genetic Diagnosis and Mitochondrial Replacementioning

confidence: 99%

Towards a therapy for mitochondrial disease: an update

Garone

Viscomi

2018

Biochemical Society Transactions

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Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.

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“…This not only demonstrated that maternally stored Hira is critical for male pronucleus formation but also provided a proof-of-principle experiment as the foundation of an approach for rescuing defects caused by impaired maternal factors. Analogous to mitochondria replacement therapy [MRT; (Greenfield et al, 2017)] we envisage that personalised medicine therapies could be applied in IVF fields in the near future. Our next steps will be to test the outcome of overexpression of other candidates such as Cabin1 or Ubn1 mutant mouse oocytes respectively, and possibly to develop nuclear transfer types of approach, such as GV transfer or spindle transfer(Costa-Borges et al, 2020), for subsequent advancement to an alternative MRT, 3 parents IVF, and other novel personalised medicine treatments.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial replacement therapy has been reported to be a substitution procedure for the rescue of oocyte inherited mitochondrial disease (Greenfield et al, 2017). We envisaged that abnormal 1PN zygote phenotypes caused by the maternal defect of Hira could potentially be rescued by overexpression in oocytes.…”

Section: Overexpression Of Hira In Mutant Oocytes Rescues Male Pronucmentioning

confidence: 99%

Histone H3.3 Hira chaperone complex contributes to zygote formation in mice and humans

Smith

Pickering

Kopakaki

et al. 2020

Preprint

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Elucidating the underlining mechanisms underpinning successful fertilisation is imperative in optimising IVF treatments, and may lead to a specific diagnosis and therefore potential treatment for some infertile couples. One of the critical steps involves paternal chromatin reprogramming, in which compacted sperm chromatin packed by protamines is removed by oocyte factors and new histones, including histone H3.3, are incorporated. This step is critical for the formation of the male pronucleus, without which the zygote contains only 1 pronucleus (1PN), in contrast to normally fertilised zygotes with two-pronuclei (2PN). 1PN zygotes are a frequently observed phenomenon in IVF treatments, therefore aberrant mechanism of action controlling paternal chromatin repackaging may be an important cause of abnormal fertilisation. Hira is the main H3.3 chaperone that governs this protamine-to-histone exchange. In this study, we investigated the maternal functions of two other molecules of the Hira complex, Cabin1 and Ubn1 in the mouse. Loss-of-function Cabin1 and Ubn1 mouse models were developed: their zygotes displayed abnormal 1PN zygote phenotypes, similar to the phenotype of Hira mutants. We then studied human 1PN zygotes, and found that the Hira complex was absent in 1PN zygotes which were lacking the male pronucleus. This result confirms that the role of the Hira complex in male pronucleus formation has coherence from mice to humans. Furthermore, rescue experiments showed that the abnormal 1PN phenotype derived from Hira mutants could be resolved by overexpression of Hira in the mouse oocytes. In summary, we have provided evidence of the role of Hira complex in regulating male pronucleus formation in both mice and humans, that both Cabin1 and Ubn1 components of the Hira complex are equally essential for male pronucleus formation, and that this can be rescued. We present a proof-of-concept experiment that could potentially lead to a personalised IVF therapy for oocyte defects.

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Assisted reproductive technologies to prevent human mitochondrial disease transmission

Cited by 90 publications

References 96 publications

1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways

1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways

Towards a therapy for mitochondrial disease: an update

Histone H3.3 Hira chaperone complex contributes to zygote formation in mice and humans

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