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Proceedings of the National Academy of... Dec 2018Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is...
Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.
Topics: Adult; Child, Preschool; DNA, Mitochondrial; Databases, Genetic; Female; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Inheritance Patterns; Male; Maternal Inheritance; Middle Aged; Mitochondria; Mitochondrial Diseases; Paternal Inheritance; Pedigree
PubMed: 30478036
DOI: 10.1073/pnas.1810946115 -
Current Opinion in Microbiology Dec 2010Faithful inheritance of mitochondria is essential for growth and development. Uniparental inheritance of mitochondria is a common phenomenon in sexual eukaryotes and has... (Review)
Review
Faithful inheritance of mitochondria is essential for growth and development. Uniparental inheritance of mitochondria is a common phenomenon in sexual eukaryotes and has been reported for numerous fungal species. Uniparental inheritance is a genetically regulated process, aimed to gain a homoplasmic state within cells, and this is often associated with selective elimination of one parental mitochondria population. This review will focus on recent developments in our understanding of common and specified regulatory circuits of selective mitochondrial inheritance during sexual development. It further refers to the influence of mitochondrial fusion on generation of recombinant mitochondrial DNA molecules. The latter aspect appears rather exciting in the context of intron homing and could bring a new twist to the debate on the significance of uniparental inheritance. The emergence of genome-wide studies offers new perspectives to address potential relationships between uniparental inheritance, vegetative inheritance and last but not least cellular scavenging systems to dispose of disintegrated organelles.
Topics: DNA, Mitochondrial; Fungi; Genes, Mitochondrial; Mitochondria; Models, Biological
PubMed: 20884279
DOI: 10.1016/j.mib.2010.09.003 -
Genome Oct 2015Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance... (Review)
Review
Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable.
Topics: Animals; DNA, Mitochondrial; Eukaryota; Evolution, Molecular; Female; Genes, Dominant; Genes, Mitochondrial; Genetic Variation; Genome, Mitochondrial; Humans; Inheritance Patterns; Male; Mitochondria; Sex Determination Processes
PubMed: 26501689
DOI: 10.1139/gen-2015-0090 -
Methods in Molecular Biology (Clifton,... 2023Mitochondria are indispensable power plants of eukaryotic cells that also act as a major biochemical hub. As such, mitochondrial dysfunction, which can originate from... (Review)
Review
Mitochondria are indispensable power plants of eukaryotic cells that also act as a major biochemical hub. As such, mitochondrial dysfunction, which can originate from mutations in the mitochondrial genome (mtDNA), may impair organism fitness and lead to severe diseases in humans. MtDNA is a multi-copy, highly polymorphic genome that is uniparentally transmitted through the maternal line. Several mechanisms act in the germline to counteract heteroplasmy (i.e., coexistence of two or more mtDNA variants) and prevent expansion of mtDNA mutations. However, reproductive biotechnologies such as cloning by nuclear transfer can disrupt mtDNA inheritance, resulting in new genetic combinations that may be unstable and have physiological consequences. Here, we review the current understanding of mitochondrial inheritance, with emphasis on its pattern in animals and human embryos generated by nuclear transfer.
Topics: Animals; Humans; Genes, Mitochondrial; Oocytes; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 37041330
DOI: 10.1007/978-1-0716-3064-8_4 -
Cell and Tissue Research May 2020Maternal mitochondrial inheritance is a fundamental paradigm within reproductive biology, yet the molecular mechanisms which underlie this process remain poorly... (Review)
Review
Maternal mitochondrial inheritance is a fundamental paradigm within reproductive biology, yet the molecular mechanisms which underlie this process remain poorly understood. The ubiquitin proteasome system (UPS) and branches of the autophagic pathway have been implicated in taking part in the active degradation of sperm mitochondria post-fertilization. Despite this knowledge, there remains much unknown about this process, including the cofactors and substrates involved, as well as the implications of what occurs when these systems of degradation fail. Mitochondrial inheritance research has utilized a variety of animal models. However, one model that is of particular importance, especially when attempting to link mitochondrial inheritance research to humans, is the domestic pig. Pigs offer relatively easy collection of gametes which are similar to those of humans. Furthermore, pigs are physiologically and anatomically more similar to humans than the majority of other model systems available. Porcine in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and novel cell-free systems are research tools which can be exploited to provide greater insight into the processes behind sperm mitochondrial degradation. In the future studies of mitochondrial inheritance, pigs will likely play a crucial role as an animal model system.
Topics: Animals; Disease Models, Animal; Genes, Mitochondrial; Humans; Sus scrofa; Swine
PubMed: 31511985
DOI: 10.1007/s00441-019-03100-z -
Trends in Microbiology Nov 2010Recent advances in yeast mitogenomics have significantly contributed to our understanding of the diversity of organization, structure and topology in the mitochondrial... (Review)
Review
Recent advances in yeast mitogenomics have significantly contributed to our understanding of the diversity of organization, structure and topology in the mitochondrial genome of budding yeasts. In parallel, new insights on mitochondrial DNA (mtDNA) inheritance in the model organism Saccharomyces cerevisiae highlighted an integrated scenario where recombination, replication and segregation of mtDNA are intricately linked to mitochondrial nucleoid (mt-nucleoid) structure and organelle sorting. In addition to this, recent discoveries of bifunctional roles of some mitochondrial proteins have interesting implications on mito-nuclear genome interactions and the relationship between mtDNA inheritance, yeast fitness and speciation. This review summarizes the current knowledge on yeast mitogenomics, mtDNA inheritance with regard to mt-nucleoid structure and organelle dynamics, and mito-nuclear genome interactions.
Topics: Cell Nucleus; Genes, Mitochondrial; Genome, Mitochondrial; Metagenomics; Mitochondria; Saccharomyces cerevisiae
PubMed: 20832322
DOI: 10.1016/j.tim.2010.08.001 -
ELife Jul 2023The degradation of sperm-borne mitochondria after fertilization is a conserved event. This process known as post-fertilization sperm mitophagy, ensures exclusively...
The degradation of sperm-borne mitochondria after fertilization is a conserved event. This process known as post-fertilization sperm mitophagy, ensures exclusively maternal inheritance of the mitochondria-harbored mitochondrial DNA genome. This mitochondrial degradation is in part carried out by the ubiquitin-proteasome system. In mammals, ubiquitin-binding pro-autophagic receptors such as SQSTM1 and GABARAP have also been shown to contribute to sperm mitophagy. These systems work in concert to ensure the timely degradation of the sperm-borne mitochondria after fertilization. We hypothesize that other receptors, cofactors, and substrates are involved in post-fertilization mitophagy. Mass spectrometry was used in conjunction with a porcine cell-free system to identify other autophagic cofactors involved in post-fertilization sperm mitophagy. This porcine cell-free system is able to recapitulate early fertilization proteomic interactions. Altogether, 185 proteins were identified as statistically different between control and cell-free-treated spermatozoa. Six of these proteins were further investigated, including MVP, PSMG2, PSMA3, FUNDC2, SAMM50, and BAG5. These proteins were phenotyped using porcine in vitro fertilization, cell imaging, proteomics, and the porcine cell-free system. The present data confirms the involvement of known mitophagy determinants in the regulation of mitochondrial inheritance and provides a master list of candidate mitophagy co-factors to validate in the future hypothesis-driven studies.
Topics: Male; Swine; Animals; Fertilization; Genes, Mitochondrial; Cell-Free System; Proteomics; Semen; Spermatozoa; DNA, Mitochondrial; Mammals; Ubiquitin
PubMed: 37470242
DOI: 10.7554/eLife.85596 -
Genetics in Medicine : Official Journal... Dec 2019A recent report has raised the possibility of biparental mitochondrial DNA (mtDNA) inheritance, which could lead to concerns by health-care professionals and patients...
PURPOSE
A recent report has raised the possibility of biparental mitochondrial DNA (mtDNA) inheritance, which could lead to concerns by health-care professionals and patients regarding investigations and genetic counseling of families with pathogenic mitochondrial DNA variants. Our aim was to examine the frequency of this phenomenon by investigating a cohort of patients with suspected mitochondrial disease.
METHODS
We studied genome sequencing (GS) data of DNA extracted from blood samples of 41 pediatric patients with suspected mitochondrial disease and their parents.
RESULTS
All of the mtDNA variants in the probands segregated with their mother or were apparently de novo. There were no variants that segregated only with the father and none of these families showed evidence of biparental inheritance of their mtDNA.
CONCLUSION
Paternal mitochondrial transmission is unlikely to be a common occurrence and therefore at this point we would not recommend changes in clinical practice.
Topics: Adult; Base Sequence; Child; Child, Preschool; DNA, Mitochondrial; Fathers; Female; Genes, Mitochondrial; Heredity; Humans; Male; Maternal Inheritance; Mitochondria; Mitochondrial Diseases; Mothers
PubMed: 31171843
DOI: 10.1038/s41436-019-0568-0 -
Advances in Experimental Medicine and... 2007Mitochondrial biogenesis and function is under dual genetic control and requires extensive interaction between biparentally inherited nuclear genes and maternally... (Review)
Review
Mitochondrial biogenesis and function is under dual genetic control and requires extensive interaction between biparentally inherited nuclear genes and maternally inherited mitochondrial genes. Standard SCNT procedures deprive an oocytes' mitochondrial DNA (mtDNA) of the corresponding maternal nuclear DNA and require it to interact with an entirely foreign nucleus that is again interacting with foreign somatic mitochondria. As a result, most SCNT embryos, -fetuses, and -offspring carry somatic cell mtDNA in addition to recipient oocyte mtDNA, a condition termed heteroplasmy. It is thus evident that somatic cell mtDNA can escape the selective mechanism that targets and eliminates intraspecific sperm mitochondria in the fertilized oocyte to maintain homoplasmy. However, the factors responsible for the large intra- and interindividual differences in heteroplasmy level remain elusive. Furthermore, heteroplasmy is probably confounded with mtDNA recombination. Considering the essential roles of mitochondria in cellular metabolism, cell signalling, and programmed cell death, future experiments will need to assess the true extent and impact of unorthodox mtDNA transmission on various aspects of SCNT success.
Topics: Animals; Cloning, Organism; Cytoplasm; DNA, Mitochondrial; Energy Metabolism; Gene Expression Regulation, Developmental; Genes, Mitochondrial; Mitochondria; Nuclear Transfer Techniques; Oocytes
PubMed: 17176558
DOI: 10.1007/978-0-387-37754-4_8 -
Advances in Experimental Medicine and... 2019The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular... (Review)
Review
The maternally inherited mitochondrial DNA (mtDNA) is located inside every mitochondrion, in variable number of copies, and it contains 37 crucial genes for cellular bioenergetics. This chapter will discuss the unique features of this circular genome including heteroplasmy, haplogroups, among others, along with the corresponding clinical relevance for each. The discussion also covers the nuclear-encoded mitochondrial genes (N > 1000) and the epistatic interactions between mtDNA and the nuclear genome. Examples of mitochondrial diseases related to specific mtDNA mutation sites of relevance for humans are provided. This chapter aims to provide an overview of mitochondrial genetics as an emerging hot topic for the future of medicine.
Topics: DNA, Mitochondrial; Energy Metabolism; Epistasis, Genetic; Genes, Mitochondrial; Genome; Humans; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 31452144
DOI: 10.1007/978-981-13-8367-0_13