scholarly journals mtDNA Heteroplasmy: Origin, Detection, Significance, and Evolutionary Consequences

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 633
Author(s):  
Maria-Eleni Parakatselaki ◽  
Emmanuel D. Ladoukakis
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Mutations ◽  
Low Frequency ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Single Type ◽  
Deleterious Mutations ◽  
Mitochondrial Replacement Therapy ◽  
Recent Method ◽  
Evolutionary Consequences

Mitochondrial DNA (mtDNA) is predominately uniparentally transmitted. This results in organisms with a single type of mtDNA (homoplasmy), but two or more mtDNA haplotypes have been observed in low frequency in several species (heteroplasmy). In this review, we aim to highlight several aspects of heteroplasmy regarding its origin and its significance on mtDNA function and evolution, which has been progressively recognized in the last several years. Heteroplasmic organisms commonly occur through somatic mutations during an individual’s lifetime. They also occur due to leakage of paternal mtDNA, which rarely happens during fertilization. Alternatively, heteroplasmy can be potentially inherited maternally if an egg is already heteroplasmic. Recent advances in sequencing techniques have increased the ability to detect and quantify heteroplasmy and have revealed that mitochondrial DNA copies in the nucleus (NUMTs) can imitate true heteroplasmy. Heteroplasmy can have significant evolutionary consequences on the survival of mtDNA from the accumulation of deleterious mutations and for its coevolution with the nuclear genome. Particularly in humans, heteroplasmy plays an important role in the emergence of mitochondrial diseases and determines the success of the mitochondrial replacement therapy, a recent method that has been developed to cure mitochondrial diseases.

scholarly journals Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

2019 ◽  
Author(s):  
Emi Ogasawara ◽  
Shun Katada ◽  
Takayuki Mito ◽  
Jun-Ichi Hayashi ◽  
Kazuto Nakada
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Large Scale ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Pathogenic Mutation ◽  
Physiological Status ◽  
Trna Genes ◽  
Diabetic Mice

AbstractMarked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion (ΔmtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying ΔmtDNA, diabetic mice carrying ΔmtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of ΔmtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.Author SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.

Mitochondrial DNA-related Disorders

2007 ◽  
Vol 27 (1-3) ◽  
pp. 31-37 ◽  
Author(s):  
Michelangelo Mancuso ◽  
Massimiliano Filosto ◽  
Anna Choub ◽  
Marta Tentorio ◽  
Laura Broglio ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Genetics ◽  
Respiratory Chain Deficiency ◽  
Clinical Syndromes ◽  
Clinical Pictures

Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as well as on a nuclear genome defect (nDNA-related disorders). mtDNA-related disorders encompass an increasing number of clinical pictures associated with more than 250 different provisional or confirmed pathogenic changes in mtDNA. Although some clinical syndromes are nosologically defined, most of the cases present with polymorphous phenotypes ranging from pure myopathy to multi-system involvement. Complexity of mitochondrial genetics is in part responsible for the extreme clinical intra- and inter-familial heterogeneity of this group of diseases. In this review, we briefly report an updated classification and overview the main clinical pictures of this class of diseases.

scholarly journals A battle for transmission: the cooperative and selfish animal mitochondrial genomes

Open Biology ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 180267 ◽  
Author(s):  
Anna Klucnika ◽  
Hansong Ma
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Energy Production ◽  
Nuclear Genome ◽  
The Other ◽  
Mitochondrial Genomes ◽  
Cellular Processes ◽  
Mitochondrial Replacement Therapy ◽  
Mtdna Evolution ◽  
Organismal Fitness

The mitochondrial genome is an evolutionarily persistent and cooperative component of metazoan cells that contributes to energy production and many other cellular processes. Despite sharing the same host as the nuclear genome, the multi-copy mitochondrial DNA (mtDNA) follows very different rules of replication and transmission, which translate into differences in the patterns of selection. On one hand, mtDNA is dependent on the host for its transmission, so selections would favour genomes that boost organismal fitness. On the other hand, genetic heterogeneity within an individual allows different mitochondrial genomes to compete for transmission. This intra-organismal competition could select for the best replicator, which does not necessarily give the fittest organisms, resulting in mito-nuclear conflict. In this review, we discuss the recent advances in our understanding of the mechanisms and opposing forces governing mtDNA transmission and selection in bilaterians, and what the implications of these are for mtDNA evolution and mitochondrial replacement therapy.

scholarly journals Mito-nuclear Incompatibilities and Mitochondrial Replacement Therapy

2016 ◽  
Author(s):  
Adam Eyre-Walker
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Replacement Therapy ◽  
Nuclear Genome ◽  
Reproductive Technology ◽  
Mitochondrial Mutations ◽  
Mitochondrial Replacement Therapy ◽  
Human Reproductive ◽  
Nuclear Genomes ◽  
Native Strains

AbstractMitochondrial replacement therapy (MRT) is a human reproductive technology by which the mitochondria of a recipient’s eggs are effectively replaced by those of a donor, potentially eliminating harmful mitochondrial mutations carried by the recipient. However, concerns have been raised that MRT may lead to problems due to incompatibilities between the nuclear genome of the recipient and mitochondrial genome of the donor. Whether this is likely to be a problem is investigated using 226 estimates, taken from the literature, of the effect of replacing the “native” by a “foreign” mitochondrial DNA (mtDNA) from the same species in a variety of animals. In approximately half of the cases (45%), strains with the foreign mtDNA have higher fitness than those with the native mtDNA, and on average the native strains are only 3% fitter. Based on these results it is argued that incompatibilities between the mitochondrial and nuclear genomes are not likely to be a problem for MRT.

Development of a mito-CRISPR system for generating mitochondrial DNA-deleted strain in Saccharomyces cerevisiae

2020 ◽  
Vol 85 (4) ◽  
pp. 895-901
Author(s):  
Takamitsu Amai ◽  
Tomoka Tsuji ◽  
Mitsuyoshi Ueda ◽  
Kouichi Kuroda
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Dna ◽  
Ethidium Bromide ◽  
Nuclear Genome ◽  
Target Sequence ◽  
Guide Rna ◽  
Crispr System ◽  
Mitochondrial Target ◽  
Gene Treatment ◽  
Mtdna Deletion

ABSTRACT Mitochondrial dysfunction can occur in a variety of ways, most often due to the deletion or mutation of mitochondrial DNA (mtDNA). The easy generation of yeasts with mtDNA deletion is attractive for analyzing the functions of the mtDNA gene. Treatment of yeasts with ethidium bromide is a well-known method for generating ρ° cells with complete deletion of mtDNA from Saccharomyces cerevisiae. However, the mutagenic effects of ethidium bromide on the nuclear genome cannot be excluded. In this study, we developed a “mito-CRISPR system” that specifically generates ρ° cells of yeasts. This system enabled the specific cleavage of mtDNA by introducing Cas9 fused with the mitochondrial target sequence at the N-terminus and guide RNA into mitochondria, resulting in the specific generation of ρ° cells in yeasts. The mito-CRISPR system provides a concise technology for deleting mtDNA in yeasts.

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.

Somatic mutations in the D-loop of mitochondrial DNA in oral squamous cell carcinoma

2011 ◽  
Vol 269 (6) ◽  
pp. 1665-1670 ◽  
Author(s):  
Shih-An Liu ◽  
Rong-San Jiang ◽  
Fun-Jou Chen ◽  
Wen-Yi Wang ◽  
Jin-Ching Lin
Keyword(s):  
Squamous Cell Carcinoma ◽  
Mitochondrial Dna ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Somatic Mutations ◽  
D Loop

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 Mitochondrial DNA Somatic Mutations (Point Mutations and Large Deletions) and Mitochondrial DNA Variants in Human Thyroid Pathology

2002 ◽  
Vol 160 (5) ◽  
pp. 1857-1865 ◽  
Author(s):  
Valdemar Máximo ◽  
Paula Soares ◽  
Jorge Lima ◽  
José Cameselle-Teijeiro ◽  
Manuel Sobrinho-Simões
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Mutations ◽  
Point Mutations ◽  
Human Thyroid ◽  
Thyroid Pathology ◽  
Large Deletions ◽  
Dna Variants ◽  
Mitochondrial Dna Variants
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