-
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 Protocols in Mouse Biology Mar 2017Mitochondrial DNA (mtDNA) lacks the protection provided by the nucleosomes in the nuclear DNA and does not have a DNA repair mechanism, making it highly susceptible to...
Mitochondrial DNA (mtDNA) lacks the protection provided by the nucleosomes in the nuclear DNA and does not have a DNA repair mechanism, making it highly susceptible to damage, which can lead to mtDNA depletion. mtDNA depletion compromises the efficient function of cells and tissues and thus impacts negatively on health. Here, we describe a brief and easy protocol to quantify mtDNA copy number by determining the mtDNA/nDNA ratio. The procedure has been validated using a cohort of young and aged mice. © 2017 by John Wiley & Sons, Inc.
Topics: Age Factors; Animals; Cell Nucleus; DNA; DNA, Mitochondrial; Gene Dosage; Genes, Mitochondrial; Mice; Polymerase Chain Reaction; Reproducibility of Results
PubMed: 28252199
DOI: 10.1002/cpmo.21 -
Nature Cell Biology Feb 2022Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate...
Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria.
Topics: Adult Stem Cells; Animals; Cell Differentiation; Cell Line; Cell Lineage; Cell Proliferation; Cellular Senescence; DNA, Mitochondrial; Energy Metabolism; Female; Genes, Mitochondrial; Humans; Mammary Glands, Human; Metabolome; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Phenotype; Proteome; Mice
PubMed: 35165416
DOI: 10.1038/s41556-021-00837-0 -
Molecular Biology and Evolution Aug 2015Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most... (Review)
Review
Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most mitochondrial genes were lost or transferred to the nucleus, but a core set of genes that code exclusively for products associated with the electron transport system remained in the mitochondrion. The products of these mitochondrial genes work in intimate association with the products of nuclear genes to enable oxidative phosphorylation and core energy production. The need for coadaptation, the challenge of cotransmission, and the possibility of genomic conflict between mitochondrial and nuclear genes have profound consequences for the ecology and evolution of eukaryotic life. An emerging interdisciplinary field that I call "mitonuclear ecology" is reassessing core concepts in evolutionary ecology including sexual reproduction, two sexes, sexual selection, adaptation, and speciation in light of the interactions of mitochondrial and nuclear genomes.
Topics: Animals; Cell Nucleus; Evolution, Molecular; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondria
PubMed: 25931514
DOI: 10.1093/molbev/msv104 -
Current Opinion in Genetics &... Jun 2023In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic... (Review)
Review
In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic conflict stemming from this transmission asymmetry is well-documented, and there is an abundance of population-genetic theory associated with it. While occasional or aberrant paternal inheritance occurs, there are only a few cases where exclusive paternal inheritance of mitochondrial genomes is the evolved state. Why this is remains poorly understood. By examining commonalities between species with exclusive paternal inheritance, we discuss what they may tell us about the evolutionary forces influencing mitochondrial inheritance patterns. We end by discussing recent technological advances that make exploring the causes and consequences of paternal inheritance feasible.
Topics: Paternal Inheritance; Mitochondria; Inheritance Patterns; Genes, Mitochondrial; Genome, Mitochondrial; DNA, Mitochondrial
PubMed: 37245242
DOI: 10.1016/j.gde.2023.102053 -
Philosophical Transactions of the Royal... Jan 2020Many conventional, modern genome engineering tools cannot be used to study mitochondrial genetics due to the unusual structure and physiology of the mitochondrial... (Review)
Review
Many conventional, modern genome engineering tools cannot be used to study mitochondrial genetics due to the unusual structure and physiology of the mitochondrial genome. Here, we review a number of newly developed, synthetic biology-based approaches for altering levels of mutant mammalian mitochondrial DNA and mitochondrial RNAs, including transcription activator-like effector nucleases, zinc finger nucleases and engineered RNA-binding proteins. These approaches allow researchers to manipulate and visualize mitochondrial processes and may provide future therapeutics. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
Topics: Animals; DNA, Mitochondrial; Gene Expression; Genes, Mitochondrial; Humans; Mammals; Mutation; Protein Engineering; RNA, Mitochondrial; RNA-Binding Proteins; Synthetic Biology; Transcription Activator-Like Effector Nucleases; Zinc Finger Nucleases
PubMed: 31787043
DOI: 10.1098/rstb.2019.0185 -
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 -
Current Neuropharmacology 2022Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics.... (Review)
Review
Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.
Topics: Amyotrophic Lateral Sclerosis; DNA, Mitochondrial; Genes, Mitochondrial; Humans; Mitochondrial Diseases; Mutation; Neurodegenerative Diseases; Parkinson Disease
PubMed: 34503413
DOI: 10.2174/1570159X19666210908163839 -
Molecular Phylogenetics and Evolution Oct 2022Molecularly, the family Caryophylliidae is polyphyletic and different sets of genetic data converge towards a consensus that a taxonomic review of this family is...
Molecularly, the family Caryophylliidae is polyphyletic and different sets of genetic data converge towards a consensus that a taxonomic review of this family is necessary. Overall, the order of genes in the mitochondrial genome (mitogenome) together with DNA sequences have been used to successfully untangle evolutionary relationships in several groups of organisms. Published mitogenomes of two caryophylliid genera (Desmophyllum and Solenosmilia) present a transposition of the gene block containing cob, nad2, and nad6, which is located between nad5 5' exon and trnW, while that of Polycyathus chaishanensis presents the same gene order as the majority of scleractinian corals. In molecular-based evolutionary reconstructions, caryophylliids that have the mitochondrial gene rearrangement were recovered as a monophyletic lineage ("true" caryophylliids), while members of the genus Polycyathus were placed in a different position. In this study, additional mitogenomes of this family were assembled and included in evolutionary reconstructions of Scleractinia in order to improve our understanding on whether the mitogenome gene rearrangement is limited to and, therefore, could be a synapomorphy of the actual members of Caryophylliidae. Specimens of Caryophyllia scobinosa, Premocyathus sp., Heterocyathus sulcatus, and Trochocyathus caryophylloides, as well as Desmophyllum pertusum and Solenosmilia variabilis from the Southwest Atlantic were sequenced using Illumina platforms. Then, mitochondrial genomes were assembled and annotated, and nuclear datasets were recovered in-silico from assembled contigs using a previously published set of baits. Evolutionary reconstructions were performed using mitochondrial and nuclear datasets and based on Maximum Likelihood and Bayesian Inference. Obtained mitogenomes are circular and range between 15,816 and 18,225 bp in size and from 30.76% to 36.63% in GC content. The gene rearrangement is only seen in C. scobinosa, D. pertusum, Premocyathus sp., and S. variabilis, which were recovered as a monophyletic clade in both mitochondrial and nuclear phylogenies. On the other hand, the "caryophylliids" with the canonical mitogenome gene order were not recovered within this clade. Differences in features of the skeleton of "true" caryophylliids in comparison to traditional members of the family were observed and offer further support that the gene rearrangement might be seen as a synapomorphy of family Caryophylliidae.
Topics: Animals; Anthozoa; Bayes Theorem; Gene Order; Genes, Mitochondrial; Genome, Mitochondrial; Phylogeny
PubMed: 35787457
DOI: 10.1016/j.ympev.2022.107565 -
Science Advances Aug 2023Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic... (Review)
Review
Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic cells.
Topics: Symbiosis; Mitochondria; Eukaryotic Cells; Genes, Mitochondrial; Phylogeny; Biological Evolution; Evolution, Molecular
PubMed: 37556561
DOI: 10.1126/sciadv.adj4493