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Journal of Biochemistry Sep 2018While the majority of DNA is enclosed within the nucleus, the mitochondria also contain their own, separate DNA, the mitochondrial DNA (mtDNA). Mutations in mtDNA are... (Review)
Review
While the majority of DNA is enclosed within the nucleus, the mitochondria also contain their own, separate DNA, the mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with various human diseases, demonstrating the importance of mtDNA. Intensive studies over the last 18 years have demonstrated the presence of two distinct classes of mtDNA replication intermediates in mammals. One involves leading-strand DNA synthesis in the absence of synchronous lagging-strand DNA synthesis. Currently there are competing models in which the lagging-strand template is either systematically hybridized to processed mitochondrial transcripts, or coated with protein, until the lagging-strand DNA synthesis takes place. The other class of mtDNA replication intermediates has many properties of conventional, coupled leading- and lagging-strand DNA synthesis. Additionally, the highly unusual arrangement of DNA in human heart mitochondria suggests a third mechanism of replication. These findings indicate that the mtDNA replication systems of humans and other mammals are far more complex than previously thought, and thereby will require further research to understand the full picture of mtDNA replication.
Topics: Animals; DNA Replication; DNA, Mitochondrial; Humans; Mammals; Mitochondria, Heart; Models, Biological; Mutation; RNA, Messenger
PubMed: 29931097
DOI: 10.1093/jb/mvy058 -
Endocrine Regulations Jul 2022Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy...
Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy in the form of adenosine triphosphate (ATP). In addition, mitochondria store calcium for the cell signaling activities, generate heat, harbor pathways of intermediate metabolism and mediate cell growth and death. Primary mitochondrial diseases (MDs) form a clinically as well as genetically heterogeneous group of inherited disorders that result from the mitochondrial energetic metabolism malfunctions. The lifetime risk of the MDs development is estimated at 1:1470 of newborns, which makes them one of the most recurrent groups of inherited disorders with an important burden for society. MDs are progressive with wide range of symptoms of variable severity that can emerge congenitally or anytime during the life. MD can be caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations inducing impairment of mitochondrial function have been found in more than 400 genes. Furthermore, more than 1200 nuclear genes, which could play a role in the MDs' genetic etiology, are involved in the mitochondrial activities. However, the knowledge regarding the mechanism of the mitochondrial pathogenicity appears to be most essential for the development of effective patient's treatment suffering from the mitochondrial disease. This is an overview update focused on the mitochondrial biology and the mitochondrial diseases associated genes.
Topics: DNA, Mitochondrial; Humans; Infant, Newborn; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 35843711
DOI: 10.2478/enr-2022-0025 -
Free Radical Biology & Medicine Jun 2017The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that... (Review)
Review
The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that can cause damage to mitochondrial DNA. If not properly repaired, the accumulation of DNA damage can lead to mitochondrial dysfunction linked to several human disorders including neurodegenerative diseases and cancer. Mitochondria are able to combat oxidative DNA damage via repair mechanisms that are analogous to those found in the nucleus. Of the repair pathways currently reported in the mitochondria, the base excision repair pathway is the most comprehensively described. Proteins that are involved with the maintenance of mtDNA are encoded by nuclear genes and translocate to the mitochondria making signaling between the nucleus and mitochondria imperative. In this review, we discuss the current understanding of mitochondrial DNA repair mechanisms and also highlight the sensors and signaling pathways that mediate crosstalk between the nucleus and mitochondria in the event of mitochondrial stress.
Topics: Cell Nucleus; DNA Damage; DNA Repair; DNA, Mitochondrial; Electron Transport Chain Complex Proteins; Energy Metabolism; Humans; Mitochondria; Neoplasms; Neurodegenerative Diseases; Reactive Oxygen Species; Signal Transduction
PubMed: 27915046
DOI: 10.1016/j.freeradbiomed.2016.11.050 -
International Journal of Molecular... Jun 2023The proper replication of mitochondrial DNA is key to the maintenance of this crucial organelle. Multiple studies aimed at understanding the mechanisms of replication of...
The proper replication of mitochondrial DNA is key to the maintenance of this crucial organelle. Multiple studies aimed at understanding the mechanisms of replication of the mitochondrial genome have been conducted in the past several decades; however, while highly informative, they were conducted using relatively low-sensitivity techniques. Here, we established a high-throughput approach based on next-generation sequencing to identify replication start sites with nucleotide-level resolution and applied it to the genome of mitochondria from different human and mouse cell types. We found complex and highly reproducible patterns of mitochondrial initiation sites, both previously annotated and newly discovered in this work, that showed differences among different cell types and species. These results suggest that the patterns of the replication initiation sites are dynamic and might reflect, in some yet unknown ways, the complexities of mitochondrial and cellular physiology. Overall, this work suggests that much remains unknown about the details of mitochondrial DNA replication in different biological states, and the method established here opens up a new avenue in the study of the replication of mitochondrial and potentially other genomes.
Topics: Animals; Humans; Mice; DNA Replication; Mitochondria; DNA, Mitochondrial; Genome, Mitochondrial; Mammals
PubMed: 37298662
DOI: 10.3390/ijms24119711 -
Current Neuropharmacology 2023Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by... (Review)
Review
Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.
Topics: Humans; Neurodegenerative Diseases; Mitochondria; Alzheimer Disease; DNA, Mitochondrial; Parkinson Disease
PubMed: 36043795
DOI: 10.2174/1570159X20666220830112408 -
American Journal of Physiology.... Jun 2021Mitochondria damage exacerbates NAFLD through trigerring AIM2 inflammasome activation and hepatocyte pyroptosis. This study provides novel insights into the underlying...
Mitochondria damage exacerbates NAFLD through trigerring AIM2 inflammasome activation and hepatocyte pyroptosis. This study provides novel insights into the underlying mechanisms of mitochondrial DNA synthesis in NAFLD and also suggests potential therapeutic targets for the treatment of NAFLD.
Topics: Animals; DNA, Mitochondrial; DNA-Binding Proteins; Diet, High-Fat; Disease Models, Animal; Hepatocytes; Inflammasomes; Male; Mice; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pyroptosis
PubMed: 33728991
DOI: 10.1152/ajpgi.00431.2020 -
Methods (San Diego, Calif.) Aug 2010The quantitative polymerase chain reaction (QPCR) assay allows measurement of DNA damage in the mitochondrial and nuclear genomes without isolation of mitochondria. It... (Review)
Review
The quantitative polymerase chain reaction (QPCR) assay allows measurement of DNA damage in the mitochondrial and nuclear genomes without isolation of mitochondria. It also permits measurement of relative mitochondrial genome copy number. Finally, it can be used for measurement of DNA repair in vivo when employed appropriately. In this manuscript we briefly review the methodology of the QPCR assay, discuss its strengths and limitations, address considerations for measurement of mitochondrial DNA repair, and describe methodological changes implemented in recent years. We present QPCR assay primers and reaction conditions for five species not previously described in a methods article: Caenorhabditis elegans, Fundulus heteroclitus, Danio rerio, Drosophila melanogaster, and adenovirus. Finally, we illustrate the use of the assay by measuring repair of ultraviolet C radiation-induced DNA damage in the nuclear but not mitochondrial genomes of a zebrafish cell culture.
Topics: Animals; Base Sequence; DNA Damage; DNA Primers; DNA Repair; DNA, Mitochondrial; Gene Dosage; Genome, Mitochondrial; Humans; Mitochondria; Polymerase Chain Reaction
PubMed: 20123023
DOI: 10.1016/j.ymeth.2010.01.033 -
Biomedical Journal Oct 2022Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human... (Review)
Review
Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human health. Mitochondrial bioenergetics is considered an important measure to assess the pathogenesis of various diseases. Dysfunctional mitochondria affect or cause several conditions involving the most energy-intensive organs, including the brain, muscles, heart, and liver. This dysfunction may be attributed to an alteration in mitochondrial enzymes, increased oxidative stress, impairment of electron transport chain and oxidative phosphorylation, or mutations in mitochondrial DNA that leads to the pathophysiology of various pathological conditions, including neurological and metabolic disorders. The drugs or compounds targeting mitochondria are considered more effective and safer for treating these diseases. In this review, we make an effort to concise the available literature on mitochondrial bioenergetics in various conditions and the therapeutic potential of various drugs/compounds targeting mitochondrial bioenergetics in metabolic and neurodegenerative diseases.
Topics: Humans; Neurodegenerative Diseases; Mitochondria; Energy Metabolism; DNA, Mitochondrial; Oxidative Phosphorylation; Oxidative Stress
PubMed: 35568318
DOI: 10.1016/j.bj.2022.05.002 -
Molecular Medicine Reports Apr 2022Mitochondria are key organelles of cellular energy metabolism; both mitochondrial function and metabolism determine the physiological function of cells and serve an... (Review)
Review
Mitochondria are key organelles of cellular energy metabolism; both mitochondrial function and metabolism determine the physiological function of cells and serve an essential role in immune responses. Key damage‑associated molecular patterns (DAMPs), such as mitochondrial DNA and N‑formyl peptides, released following severe trauma‑induced mitochondrial damage may affect the respiratory chain, enhance oxidative stress and activate systemic inflammatory responses via a variety of inflammation‑associated signaling pathways. Severe trauma can lead to sepsis, multiple organ dysfunction syndrome and death. The present review aimed to summarize the pathophysiological mechanisms underlying the effects of human mitochondrial injury‑released DAMPs on triggering systemic inflammatory responses and to determine their potential future clinical applications in preventing and treating sepsis.
Topics: Alarmins; DNA, Mitochondrial; Humans; Inflammation; Mitochondria; Sepsis
PubMed: 35234261
DOI: 10.3892/mmr.2022.12663 -
Free Radical Biology & Medicine Aug 2015In the past century, considerable efforts were made to understand the role of mitochondrial DNA (mtDNA) mutations and of oxidative stress in aging. The classic... (Review)
Review
In the past century, considerable efforts were made to understand the role of mitochondrial DNA (mtDNA) mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the past few years, however, new elements have discredited this original theory. The major sources of mitochondrial DNA mutations seem to be replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms seems to occur by clonal expansion and not to be caused by a reactive oxygen species-dependent vicious cycle. New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.
Topics: Animals; Cellular Senescence; DNA Damage; DNA Repair; DNA, Mitochondrial; Humans; Reactive Oxygen Species
PubMed: 25979659
DOI: 10.1016/j.freeradbiomed.2015.05.005