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International Journal of Molecular... May 2023In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm...
In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm-oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation.
Topics: Humans; Male; Female; Semen; Infertility; Mitochondria; DNA, Mitochondrial; Oocytes; Fertility
PubMed: 37240296
DOI: 10.3390/ijms24108950 -
Medecine Sciences : M/S Mar 2021DNA methylation is an epigenetic mechanism that has been largely probed regarding eukaryotic nuclear genome and bacteria, and its role is especially crucial in the... (Review)
Review
DNA methylation is an epigenetic mechanism that has been largely probed regarding eukaryotic nuclear genome and bacteria, and its role is especially crucial in the regulation of gene expression. In mammals, it is almost exclusively acting on a cytosine preceding a guanine (CpG), whereas it presents itself mainly in a non-CpG context in bacteria's DNA. Conversely to nuclear and bacterial genomes, the existence of methylation in the mitochondrial genome is still widely debated. This controversy has been attributed to structural differences between the nuclear and mitochondrial genomes, and to the techniques used to study methylation of cytosines, which were rather optimized for the study of nuclear DNA. However, novel studies suggest that cytosine methylation is truly existing in mitochondria, and that it is mostly found in a non-CpG context, just like in their evolutionary relative, the bacteria.
Topics: DNA Methylation; DNA, Mitochondrial
PubMed: 33739273
DOI: 10.1051/medsci/2021011 -
Neuron Dec 2014Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial... (Review)
Review
Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA (mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy.
Topics: Central Nervous System; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Models, Genetic; Mutation; Peripheral Nervous System
PubMed: 25521375
DOI: 10.1016/j.neuron.2014.11.022 -
Genome Aug 2020We review the insertion of mitochondrial DNA (mtDNA) fragments into nuclear DNA (NUMTS) as a general and ongoing process that has occurred many times during genome... (Review)
Review
We review the insertion of mitochondrial DNA (mtDNA) fragments into nuclear DNA (NUMTS) as a general and ongoing process that has occurred many times during genome evolution. Fragments of mtDNA are generated during the lifetime of organisms in both somatic and germinal cells, by the production of reactive oxygen species in the mitochondria. The fragments are inserted into the nucleus during the double-strand breaks repair via the non-homologous end-joining machinery, followed by genomic instability, giving rise to the high variability observed in NUMT patterns among species, populations, or genotypes. Some de novo produced mtDNA insertions show harmful effects, being involved in human diseases, carcinogenesis, and ageing. NUMT generation is a non-stop process overpassing the Mendelian transmission. This parasitic property ensures their survival even against their harmful effects. The accumulation of mtDNA fragments mainly at pericentromeric and subtelomeric regions is important to understand the transmission and integration of NUMTs into the genomes. The possible effect of female meiotic drive for mtDNA insertions at centromeres remains to be studied. In spite of the harmful feature of NUMTs, they are important in cell evolution, representing a major source of genomic variation.
Topics: Aging; Animals; Cell Nucleus; Centromere; DNA, Mitochondrial; Disease; Evolution, Molecular; Humans; Mutagenesis, Insertional; Telomere
PubMed: 32396758
DOI: 10.1139/gen-2019-0151 -
Cell Metabolism Nov 2022Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited,...
Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a conserved quality control mechanism that remains poorly understood. Here, through a large-scale screen, we uncover a unique programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We find that PGM is developmentally triggered as germ cells enter meiosis by inhibition of the target of rapamycin complex 1 (TORC1). We identify a role for the RNA-binding protein Ataxin-2 (Atx2) in coordinating the timing of PGM with meiosis. We show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission and translation factors, and members of the Atg1 complex, but not the mitophagy factors PINK1 and Parkin. Additionally, we report several factors that are critical for germline mtDNA quality control and show that pharmacological manipulation of one of these factors promotes mtDNA quality control.
Topics: Mitophagy; DNA, Mitochondrial; Mitochondria; Ubiquitin-Protein Ligases; Germ Cells; Quality Control
PubMed: 36323236
DOI: 10.1016/j.cmet.2022.10.005 -
Scientific Reports Nov 2016Cell free DNA (cfDNA) has received increasing attention and has been studied in a broad range of clinical conditions. However, few studies have focused on mitochondrial...
Cell free DNA (cfDNA) has received increasing attention and has been studied in a broad range of clinical conditions. However, few studies have focused on mitochondrial DNA (mtDNA) in the cell free form. We optimized DNA isolation and sequencing library preparation protocols to better retain short DNA fragments from plasma, and applied these optimized methods to plasma samples from patients with sepsis. Our methods can retain substantially shorter DNA, resulting in an average of 11.5 fold increase in short DNA fragments yield (DNA <100bp). We report that cf-mtDNA in plasma is highly enriched in short-size cfDNA (30~60 bp). Motivated by this unique size distribution, we size-selected short cfDNA, which further increased the mtDNA recovery rate by an average of 10.4 fold. We then detected mtDNA heteroplasmy in plasma from 3 patients. In one patient who previously received bone marrow transplantation, different minor allele frequencies were observed between plasma and leukocytes at heteroplasmic sites, consistent with mixed-tissue origin for cfDNA. For the other two patients, the heteroplasmy pattern is also different between plasma and leukocyte. Our study shed new lights into the architecture of the cfDNA, and mtDNA heteroplasmy identified in plasma provides new potential for biomarker discovery.
Topics: Bone Marrow Transplantation; Cell-Free Nucleic Acids; DNA, Mitochondrial; Gene Frequency; Genetic Variation; High-Throughput Nucleotide Sequencing; Humans; Leukocytes; Molecular Weight; Mutation; Plasma; Sequence Analysis, DNA; Transplantation Chimera
PubMed: 27811968
DOI: 10.1038/srep36097 -
Cell Death and Differentiation Nov 2013DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the... (Review)
Review
DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.
Topics: Animals; Autophagy; Carcinogenesis; DNA Damage; DNA Repair; DNA, Mitochondrial; Genomic Instability; Humans
PubMed: 23933813
DOI: 10.1038/cdd.2013.103 -
Journal of Translational Medicine May 2023Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are... (Review)
Review
Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are formed to carry the malfunctioned mitochondrial components, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be eliminated to restore normal mitochondrial structure and functions. Under severe oxidative stress condition, mitochondrial dynamics (fission/fusion) and mitophagy are predominantly activated to rescue mitochondrial structure and functions. Additionally, MDVs generation can be also triggered as the major MQC machinery to cope with unhealthy mitochondria when mitophagy is unsuccessful for eliminating the damaged mitochondria or mitochondrial fission/fusion fail to recover the mitochondrial structure and functions. This review summarizes the current knowledge on MDVs and discuss their roles in physiologic and pathophysiologic conditions. In addition, the potential clinical relevance of MDVs in therapeutics and diagnostics of kidney stone disease (KSD) are emphasized.
Topics: Humans; Mitochondria; Oxidative Stress; DNA, Mitochondrial; Mitophagy; Kidney Calculi
PubMed: 37131163
DOI: 10.1186/s12967-023-04133-3 -
International Journal of Molecular... Oct 2022Mitochondrial abnormalities are primarily seen in morphology, structure and function. They can cause damage to organs, including the heart, brain and muscle, by various...
Mitochondrial abnormalities are primarily seen in morphology, structure and function. They can cause damage to organs, including the heart, brain and muscle, by various mechanisms, such as oxidative stress, abnormal energy metabolism, or genetic mutations. Identifying and detecting pathophysiological alterations in mitochondria is the principal means of studying mitochondrial abnormalities. The present study reviewed methods in mitochondrial research and focused on three aspects: Mitochondrial extraction and purification, morphology and structure and function. In addition to classical methods, such as electron microscopy and mitochondrial membrane potential monitoring, newly developed methods, such as mitochondrial ultrastructural determination, mtDNA mutation assays, metabolomics and analyses of regulatory mechanisms, have also been utilized in recent years. These approaches enable the accurate detection of mitochondrial abnormalities and provide guidance for the diagnosis and treatment of related diseases.
Topics: DNA, Mitochondrial; Membrane Potential, Mitochondrial; Mitochondria; Mutation; Oxidative Stress
PubMed: 36004457
DOI: 10.3892/ijmm.2022.5182 -
Journal of Cerebral Blood Flow and... Sep 2022Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al....
Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al. reported a novel method for single cells mitochondria transplantation using "nanosyringe". This technique combines atomic force microscopy, optical microscopy, and nanofluidics that enable intra- and intercellular organelle micromanipulation and cell-to-cell mitochondria transplantation with up to 95% success rate. The transferred mitochondria fuse to the host mitochondrial network and donor mtDNA incorporate into the recipient mitochondrial genome. The nanosyringe technique provides a novel tool for future mitochondrial research to offer insight into mitochondrial replacement therapy for stroke and fundamental mitochondrial biology.
Topics: DNA, Mitochondrial; Mitochondria
PubMed: 35726581
DOI: 10.1177/0271678X221109685