scholarly journals Mitochondrial DNA Replacement Techniques to Prevent Human Mitochondrial Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 551
Author(s):  
Luis Sendra ◽  
Alfredo García-Mares ◽  
María José Herrero ◽  
Salvador F. Aliño
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Genetic Disorders ◽  
Mitochondrial Diseases ◽  
Legal Regulation ◽  
Donor Oocyte ◽  
Legal Position ◽  
Ethical And Legal Issues ◽  
Mitochondrial Replacement Techniques ◽  
Do So

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required.

scholarly journals Does egg donation for mitochondrial replacement techniques generate parental responsibilities?

2017 ◽  
Vol 44 (12) ◽  
pp. 817-822 ◽  
Author(s):  
César Palacios-González
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Mitochondrial Diseases ◽  
Egg Donation ◽  
Genetic Composition ◽  
Numerical Identity ◽  
Egg Donor ◽  
Egg Donors ◽  
Mitochondrial Replacement Techniques

Children created through mitochondrial replacement techniques (MRTs) are commonly presented as possessing 50% of their mother’s nuclear DNA, 50% of their father’s nuclear DNA and the mitochondrial DNA of an egg donor. This lab-engineered genetic composition has prompted two questions: Do children who are the product of an MRT procedure have three genetic parents? And, do MRT egg donors have parental responsibilities for the children created? In this paper, I address the second question and in doing so I also address the first one. First, I present a brief account of mitochondrial diseases and MRTs. Second, I examine how MRTs affect the numerical identity of eggs and zygotes. Third, I investigate two genetic accounts of parenthood and MRT egg donation. Fourth, I explore three causal accounts of parenthood and MRT egg donation. My conclusion is that, under the appropriate circumstances, MRT egg donors are parentally responsible for the children created under genetic accounts of parenthood and under causal accounts of parenthood.

scholarly journals Clinical Utility of Rapid Exome Sequencing Combined With Mitochondrial DNA Sequencing in Critically Ill Pediatric Patients With Suspected Genetic Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuejun Ouyang ◽  
Yu Zhang ◽  
Lijuan Zhang ◽  
Jixuan Luo ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Differential Diagnosis ◽  
Dna Sequencing ◽  
Exome Sequencing ◽  
Critically Ill ◽  
Clinical Utility ◽  
Pediatric Patients ◽  
Genetic Disorders ◽  
Mitochondrial Diseases ◽  
Mtdna Mutation

Genetic disorders are a frequent cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU). In recent years, rapid genome-wide sequencing (exome or whole genome sequencing) has been applied in the NICU/PICU. However, mtDNA sequencing is not routinely available in rapid genetic diagnosis programs, which may fail to diagnose mtDNA mutation-associated diseases. Herein, we explored the clinical utility of rapid exome sequencing combined with mtDNA sequencing in critically ill pediatric patients with suspected genetic disorders. Rapid clinical exome sequencing (CES) was performed as a first-tier test in 40 critically ill pediatric patients (aged from 6 days to 15 years) with suspected genetic conditions. Blood samples were also collected from the parents for trio analysis. Twenty-six patients presented with neuromuscular abnormalities or other systemic abnormalities, suggestive of suspected mitochondrial diseases or the necessity for a differential diagnosis of other diseases, underwent rapid mtDNA sequencing concurrently. A diagnosis was made in 18 patients (45.0%, 18/40); three cases with de novo autosomal dominant variants, ten cases with homozygous or compound heterozygous variants, three cases with hemizygous variants inherited from mother, three cases with heterozygous variants inherited from either parent, and one case with a mtDNA mutation. The 18 patients were diagnosed with metabolic (n = 7), immunodeficiency (n = 4), cardiovascular (n = 2), neuromuscular (n = 2) disorders, and others. Genetic testing reports were generated with a median time of 5 days (range, 3–9 days). Thirteen patients that were diagnosed had an available medical treatment and resulted in a positive outcome. We propose that rapid exome sequencing combined with mitochondrial DNA sequencing should be available to patients with suspected mitochondrial diseases or undefined clinical features necessary for making a differential diagnosis of other diseases.

scholarly journals Lesbian motherhood and mitochondrial replacement techniques: reproductive freedom and genetic kinship

2018 ◽  
Vol 44 (12) ◽  
pp. 835-842 ◽  
Author(s):  
Giulia Cavaliere ◽  
César Palacios-González
Keyword(s):  
Mitochondrial Dna ◽  
Therapeutic Potential ◽  
Mitochondrial Diseases ◽  
Sufficient Reason ◽  
Lesbian Couples ◽  
Reproductive Freedom ◽  
Lesbian Motherhood ◽  
Genetic Parenthood ◽  
Mitochondrial Replacement Techniques ◽  
Potential Objection

In this paper, we argue that lesbian couples who wish to have children who are genetically related to both of them should be allowed access to mitochondrial replacement techniques (MRTs). First, we provide a brief explanation of mitochondrial diseases and MRTs. We then present the reasons why MRTs are not, by nature, therapeutic. The upshot of the view that MRTs are non-therapeutic techniques is that their therapeutic potential cannot be invoked for restricting their use only to those cases where a mitochondrial DNA disease could be ‘cured’. We then argue that a positive case for MRTs is justified by an appeal to reproductive freedom, and that the criteria to access these techniques should hence be extended to include lesbian couples who wish to share genetic parenthood. Finally, we consider a potential objection to our argument: that the desire to have genetically related kin is not a morally sufficient reason to allow lesbian couples to access MRTs.

scholarly journals A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations

2021 ◽  
Vol 22 (9) ◽  
pp. 4461
Author(s):  
Giulia di Punzio ◽  
Maria Antonietta Di Noia ◽  
Agnès Delahodde ◽  
Carole Sellem ◽  
Claudia Donnini ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
De Novo ◽  
Mitochondrial Diseases ◽  
Spontaneous Mutations ◽  
Yeast Mutant ◽  
Heterozygous Condition ◽  
Therapeutic Drugs ◽  
Therapeutic Molecules ◽  
Growth Phenotype

Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations.

scholarly journals Treatment for mitochondrial diseases

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Tongling Liufu ◽  
Zhaoxia Wang
Keyword(s):  
Clinical Trials ◽  
Nuclear Dna ◽  
Mitochondrial Diseases ◽  
Cochrane Collaboration ◽  
Potential Bias ◽  
Leber Hereditary Optic Neuropathy ◽  
Pharmacological Agents ◽  
Unpublished Studies ◽  
New Treatment ◽  
Allotopic Expression

AbstractMitochondrial diseases are predominantly caused by mutations of mitochondrial or nuclear DNA, resulting in multisystem defects. Current treatments are largely supportive, and the disorders progress relentlessly. Nutritional supplements, pharmacological agents and physical therapies have been used in different clinical trials, but the efficacy of these interventions need to be further evaluated. Several recent reviews discussed some of the interventions but ignored bias in those trials. This review was conducted to discover new studies and grade the original studies for potential bias with revised Cochrane Collaboration guidelines. We focused on seven published studies and three unpublished studies; eight of these studies showed improvement in outcome measurements. In particular, two of the interventions have been tested in studies with strict design, which we believe deserve further clinical trials with a large sample. Additionally, allotopic expression of the ND4 subunit seemed to be an effective new treatment for patients with Leber hereditary optic neuropathy.

scholarly journals The Role of Mitochondria in Carcinogenesis

2021 ◽  
Vol 22 (10) ◽  
pp. 5100
Author(s):  
Paulina Kozakiewicz ◽  
Ludmiła Grzybowska-Szatkowska ◽  
Marzanna Ciesielka ◽  
Jolanta Rzymowska
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Dna Polymorphisms ◽  
Gene Encoding ◽  
Dna Mutations ◽  
Nadh Ubiquinone Oxidoreductase ◽  
Gene Coi ◽  
The Impact

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

Evidence for genetic hybridization between Ixodes scapularis and Ixodes cookei

2017 ◽  
Vol 95 (8) ◽  
pp. 527-537 ◽  
Author(s):  
James W. Patterson ◽  
Anna M. Duncan ◽  
Kelsey C. McIntyre ◽  
Vett K. Lloyd
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Analysis ◽  
New Brunswick ◽  
Nuclear Dna ◽  
Ixodes Scapularis ◽  
Companion Animals ◽  
Genetic Introgression ◽  
Eastern Canada ◽  
As Species ◽  
Intermediate Traits

Ixodes scapularis Say, 1821 (the black-legged tick) is becoming established in Canada. The northwards expansion of I. scapularis leads to contact between I. scapularis and Ixodes cookei Packard, 1869, a well-established tick species in Eastern Canada. Examination of I. cookei and I. scapularis collected from New Brunswick revealed ticks with ambiguous morphologies, with either a mixture or intermediate traits typical of I. scapularis and I. cookei, including in characteristics typically used as species identifiers. Genetic analysis to determine if these ticks represent hybrids revealed that four had I. cookei derived mitochondrial DNA but I. scapularis nuclear DNA. In one case, the nuclear sequence showed evidence of heterozygosity for I. scapularis and I. cookei sequences, whereas in the others, the nuclear DNA appeared to be entirely derived from I. scapularis. These data strongly suggest genetic hybridization between these two species. Ixodes cookei and hybrid ticks were readily collected from humans and companion animals and specimens infected with Borrelia burgdorferi Johnson et al., 1984, the causative agent of Lyme disease, were identified. These findings raise the issue of genetic introgression of I. scapularis genes into I. cookei and warrant reassessment of the capacity of I. cookei and I. cookei × I. scapularis hybrids to vector Borrelia infection.

scholarly journals Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

2021 ◽  
Author(s):  
George B. Stefano ◽  
Richard M. Kream
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Neurological Disorders ◽  
Nuclear Dna ◽  
Mitochondrial Dynamics ◽  
Cell Types ◽  
Tissue Specific ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

scholarly journals Mitochondrial DNA Methylation and Human Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4594
Author(s):  
Andrea Stoccoro ◽  
Fabio Coppedè
Keyword(s):  
Dna Methylation ◽  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Nuclear Genome ◽  
Epigenetic Modifications ◽  
Human Diseases ◽  
Loop Region ◽  
D Loop

Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

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