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1
Faria, Rúben, Eric Vivés, Prisca Boisguerin, Angela Sousa e Diana Costa. "Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery". Polymers 13, n. 11 (1 giugno 2021): 1836. http://dx.doi.org/10.3390/polym13111836.
Testo completoAbstract (sommario):
A mitochondrion is a cellular organelle able to produce cellular energy in the form of adenosine triphosphate (ATP). As in the nucleus, mitochondria contain their own genome: the mitochondrial DNA (mtDNA). This genome is particularly susceptible to mutations that are at the basis of a multitude of disorders, especially those affecting the heart, the central nervous system and muscles. Conventional clinical practice applied to mitochondrial diseases is very limited and ineffective; a clear need for innovative therapies is demonstrated. Gene therapy seems to be a promising approach. The use of mitochondrial DNA as a therapeutic, optimized by peptide-based complexes with mitochondrial targeting, can be seen as a powerful tool in the reestablishment of normal mitochondrial function. In line with this requirement, in this work and for the first time, a mitochondrial-targeting sequence (MTS) has been incorporated into previously researched peptides, to confer on them a targeting ability. These peptides were then considered to complex a plasmid DNA (pDNA) which contains the mitochondrial gene ND1 (mitochondrially encoded NADH dehydrogenase 1 protein), aiming at the formation of peptide-based nanoparticles. Currently, the ND1 plasmid is one of the most advanced bioengineered vectors for conducting research on mitochondrial gene expression. The formed complexes were characterized in terms of pDNA complexation capacity, morphology, size, surface charge and cytotoxic profile. These data revealed that the developed carriers possess suitable properties for pDNA delivery. Furthermore, in vitro studies illustrated the mitochondrial targeting ability of the novel peptide/pDNA complexes. A comparison between the different complexes revealed the most promising ones that complex pDNA and target mitochondria. This may contribute to the optimization of peptide-based non-viral systems to target mitochondria, instigating progress in mitochondrial gene therapy.
2
Basu, Urmimala, Alicia M. Bostwick, Kalyan Das, Kristin E. Dittenhafer-Reed e Smita S. Patel. "Structure, mechanism, and regulation of mitochondrial DNA transcription initiation". Journal of Biological Chemistry 295, n. 52 (30 ottobre 2020): 18406–25. http://dx.doi.org/10.1074/jbc.rev120.011202.
Testo completoAbstract (sommario):
Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.
3
Campbell, C. L., e P. E. Thorsness. "Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments". Journal of Cell Science 111, n. 16 (15 agosto 1998): 2455–64. http://dx.doi.org/10.1242/jcs.111.16.2455.
Testo completoAbstract (sommario):
Inactivation of Yme1p, a mitochondrially-localized ATP-dependent metallo-protease in the yeast Saccharomyces cerevisiae, causes a high rate of DNA escape from mitochondria to the nucleus as well as pleiotropic functional and morphological mitochondrial defects. The evidence presented here suggests that the abnormal mitochondria of a yme1 strain are degraded by the vacuole. First, electron microscopy of Yme1p-deficient strains revealed mitochondria physically associated with the vacuole via electron dense structures. Second, disruption of vacuolar function affected the frequency of mitochondrial DNA escape from yme1 and wild-type strains. Both PEP4 or PRC1 gene disruptions resulted in a lower frequency of mitochondrial DNA escape. Third, an in vivo assay that monitors vacuole-dependent turnover of the mitochondrial compartment demonstrated an increased rate of mitochondrial turnover in yme1 yeast when compared to the rate found in wild-type yeast. In this assay, vacuolar alkaline phosphatase, encoded by PHO8, was targeted to mitochondria in a strain bearing disruption to the genomic PHO8 locus. Maturation of the mitochondrially localized alkaline phosphatase pro-enzyme requires proteinase A, which is localized in the vacuole. Therefore, alkaline phosphatase activity reflects vacuole-dependent turnover of mitochondria. This assay reveals that mitochondria of a yme1 strain are taken up by the vacuole more frequently than mitochondria of an isogenic wild-type strain when these yeast are cultured in medium necessitating respiratory growth. Degradation of abnormal mitochondria is one pathway by which mitochondrial DNA escapes and migrates to the nucleus.
4
Herrmann, J. M., R. A. Stuart, E. A. Craig e W. Neupert. "Mitochondrial heat shock protein 70, a molecular chaperone for proteins encoded by mitochondrial DNA." Journal of Cell Biology 127, n. 4 (15 novembre 1994): 893–902. http://dx.doi.org/10.1083/jcb.127.4.893.
Testo completoAbstract (sommario):
Mitochondrial heat shock protein 70 (mt-Hsp70) has been shown to play an important role in facilitating import into, as well as folding and assembly of nuclear-encoded proteins in the mitochondrial matrix. Here, we describe a role for mt-Hsp70 in chaperoning proteins encoded by mitochondrial DNA and synthesized within mitochondria. The availability of mt-Hsp70 function influences the pattern of proteins synthesized in mitochondria of yeast both in vivo and in vitro. In particular, we show that mt-Hsp70 acts in maintaining the var1 protein, the only mitochondrially encoded subunit of mitochondrial ribosomes, in an assembly competent state, especially under heat stress conditions. Furthermore, mt-Hsp70 helps to facilitate assembly of mitochondrially encoded subunits of the ATP synthase complex. By interacting with the ATP-ase 9 oligomer, mt-Hsp70 promotes assembly of ATP-ase 6, and thereby protects the latter protein from proteolytic degradation. Thus mt-Hsp70 by acting as a chaperone for proteins encoded by the mitochondrial DNA, has a critical role in the assembly of supra-molecular complexes.
5
Varma, V. A., C. M. Cerjan, K. L. Abbott e S. B. Hunter. "Non-isotopic in situ hybridization method for mitochondria in oncocytes." Journal of Histochemistry & Cytochemistry 42, n. 2 (febbraio 1994): 273–76. http://dx.doi.org/10.1177/42.2.8288868.
Testo completoAbstract (sommario):
We used in situ hybridization to specifically identify mitochondria in a series of formalin-fixed, paraffin-embedded oncocytic lesions. Digoxigenin-labeled DNA probes were generated by the polymerase chain reaction (PCR), with primers designed to amplify a mitochondrion-specific 154 BP sequence within the ND4 coding region. Probes were hybridized with mitochondrial DNA under stringent conditions. Oncocytes were strongly and consistently stained, reflecting the high copy number of mitochondrial DNA within these cells. Because of the presence of endogenous biotin within mitochondria, digoxigenin is preferable to biotin as a label for detection of mitochondria.
6
Habbane, Mouna, Julio Montoya, Taha Rhouda, Yousra Sbaoui, Driss Radallah e Sonia Emperador. "Human Mitochondrial DNA: Particularities and Diseases". Biomedicines 9, n. 10 (1 ottobre 2021): 1364. http://dx.doi.org/10.3390/biomedicines9101364.
Testo completoAbstract (sommario):
Mitochondria are the cell’s power site, transforming energy into a form that the cell can employ for necessary metabolic reactions. These organelles present their own DNA. Although it codes for a small number of genes, mutations in mtDNA are common. Molecular genetics diagnosis allows the analysis of DNA in several areas such as infectiology, oncology, human genetics and personalized medicine. Knowing that the mitochondrial DNA is subject to several mutations which have a direct impact on the metabolism of the mitochondrion leading to many diseases, it is therefore necessary to detect these mutations in the patients involved. To date numerous mitochondrial mutations have been described in humans, permitting confirmation of clinical diagnosis, in addition to a better management of the patients. Therefore, different techniques are employed to study the presence or absence of mitochondrial mutations. However, new mutations are discovered, and to determine if they are the cause of disease, different functional mitochondrial studies are undertaken using transmitochondrial cybrid cells that are constructed by fusion of platelets of the patient that presents the mutation, with rho osteosarcoma cell line. Moreover, the contribution of next generation sequencing allows sequencing of the entire human genome within a single day and should be considered in the diagnosis of mitochondrial mutations.
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Hong, Seongho, Sanghun Kim, Kyoungmi Kim e Hyunji Lee. "Clinical Approaches for Mitochondrial Diseases". Cells 12, n. 20 (20 ottobre 2023): 2494. http://dx.doi.org/10.3390/cells12202494.
Testo completoAbstract (sommario):
Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform ‘oxidative phosphorylation (OX PHOS)’, which are expressed by the mitochondria’s self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.
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Wang, Sheng-Fan, Shiuan Chen, Ling-Ming Tseng e Hsin-Chen Lee. "Role of the mitochondrial stress response in human cancer progression". Experimental Biology and Medicine 245, n. 10 (23 aprile 2020): 861–78. http://dx.doi.org/10.1177/1535370220920558.
Testo completoAbstract (sommario):
Mitochondria are important organelles that are responsible for cellular energy metabolism, cellular redox/calcium homeostasis, and cell death regulation in mammalian cells. Mitochondrial dysfunction is involved in various diseases, such as neurodegenerative diseases, cardiovascular diseases, immune disorders, and cancer. Defective mitochondria and metabolism remodeling are common characteristics in cancer cells. Several factors, such as mitochondrial DNA copy number changes, mitochondrial DNA mutations, mitochondrial enzyme defects, and mitochondrial dynamic changes, may contribute to mitochondrial dysfunction in cancer cells. Some lines of evidence have shown that mitochondrial dysfunction may promote cancer progression. Here, several mitochondrial stress responses, including the mitochondrial unfolded protein response and the integrated stress response, and several mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and others) are reviewed; these pathways and molecules are considered to act as retrograde signaling regulators in the development and progression of cancer. Targeting these components of the mitochondrial stress response may be an important strategy for cancer treatment. Impact statement Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.
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Bradshaw, Patrick C., e David C. Samuels. "A computational model of mitochondrial deoxynucleotide metabolism and DNA replication". American Journal of Physiology-Cell Physiology 288, n. 5 (maggio 2005): C989—C1002. http://dx.doi.org/10.1152/ajpcell.00530.2004.
Testo completoAbstract (sommario):
We present a computational model of mitochondrial deoxynucleotide metabolism and mitochondrial DNA (mtDNA) synthesis. The model includes the transport of deoxynucleosides and deoxynucleotides into the mitochondrial matrix space, as well as their phosphorylation and polymerization into mtDNA. Different simulated cell types (cancer, rapidly dividing, slowly dividing, and postmitotic cells) are represented in this model by different cytoplasmic deoxynucleotide concentrations. We calculated the changes in deoxynucleotide concentrations within the mitochondrion during the course of a mtDNA replication event and the time required for mtDNA replication in the different cell types. On the basis of the model, we define three steady states of mitochondrial deoxynucleotide metabolism: the phosphorylating state (the net import of deoxynucleosides and export of phosphorylated deoxynucleotides), the desphosphorylating state (the reverse of the phosphorylating state), and the efficient state (the net import of both deoxynucleosides and deoxynucleotides). We present five testable hypotheses based on this simulation. First, the deoxynucleotide pools within a mitochondrion are sufficient to support only a small fraction of even a single mtDNA replication event. Second, the mtDNA replication time in postmitotic cells is much longer than that in rapidly dividing cells. Third, mitochondria in dividing cells are net sinks of cytoplasmic deoxynucleotides, while mitochondria in postmitotic cells are net sources. Fourth, the deoxynucleotide carrier exerts the most control over the mtDNA replication rate in rapidly dividing cells, but in postmitotic cells, the NDPK and TK2 enzymes have the most control. Fifth, following from the previous hypothesis, rapidly dividing cells derive almost all of their mtDNA precursors from the cytoplasmic deoxynucleotides, not from phosphorylation within the mitochondrion.
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Bertrand, Helmut. "Senescence is coupled to induction of an oxidative phosphorylation stress response by mitochondrial DNA mutations in Neurospora". Canadian Journal of Botany 73, S1 (31 dicembre 1995): 198–204. http://dx.doi.org/10.1139/b95-246.
Testo completoAbstract (sommario):
In Neurospora and other genera of filamentous fungi, the occurrence of a mutation affecting one or several genes on the chromosome of a single mitochondrion can trigger the gradual displacement of wild-type mitochondrial DNA by mutant molecules in asexually propagated cultures. As this displacement progresses, the cultures senesce gradually and die if the mitochondrial mutation is lethal, or develop respiratory deficiencies if the mutation is nonlethal. Mitochondrial mutations that elicit the displacement of wild-type mitochondrial DNAs are said to be "suppressive." In the strictly aerobic fungi, suppressiveness appears to be associated exclusively with mutations that diminish cytochrome-mediated mitochondrial redox functions and, thus, curtail oxidative phosphorylation. In Neurospora, suppressiveness is connected to a regulatory system through which cells respond to chemical or genetic insults to the mitochondrial electron-transport system by increasing the number of mitochondria approximately threefold. Mutant alleles of two nuclear genes, osr-1 and osr-2, affect this stress response and abrogate the suppressiveness of mitochondrial mutations. Therefore, we propose that mitochondrial mutations are suppressive because their phenotypic effect is limited to the organelles within which the mutant DNA is located. Consequently, mitochondria that are "homozygous" for a mutant allele are functionally crippled and are induced to proliferate more rapidly than the normal mitochondria with which they coexist in a common protoplasm. While this model provides a plausible explanation for the suppressiveness of mitochondrial mutations in the strictly aerobic fungi, it may not account for the biased transmission of mutant mitochondrial DNAs in the facultatively anaerobic yeasts. Key words: mitochondria, mitochondrial DNA, mutations, suppressiveness, oxidative phosphorylation, stress response.
11
Shimura, Tsutomu. "Mitochondrial Signaling Pathways Associated with DNA Damage Responses". International Journal of Molecular Sciences 24, n. 7 (24 marzo 2023): 6128. http://dx.doi.org/10.3390/ijms24076128.
Testo completoAbstract (sommario):
Under physiological and stress conditions, mitochondria act as a signaling platform to initiate biological events, establishing communication from the mitochondria to the rest of the cell. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species, cytochrome C, and damage-associated molecular patterns act as messengers in metabolism, oxidative stress response, bystander response, apoptosis, cellular senescence, and inflammation response. In this review paper, the mitochondrial signaling in response to DNA damage was summarized. Mitochondrial clearance via fusion, fission, and mitophagy regulates mitochondrial quality control under oxidative stress conditions. On the other hand, damaged mitochondria release their contents into the cytoplasm and then mediate various signaling pathways. The role of mitochondrial dysfunction in radiation carcinogenesis was discussed, and the recent findings on radiation-induced mitochondrial signaling and radioprotective agents that targeted mitochondria were presented. The analysis of the mitochondrial radiation effect, as hypothesized, is critical in assessing radiation risks to human health.
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Khotina, Victoria A., Andrey Y. Vinokurov, Mariam Bagheri Ekta, Vasily N. Sukhorukov e Alexander N. Orekhov. "Creation of Mitochondrial Disease Models Using Mitochondrial DNA Editing". Biomedicines 11, n. 2 (12 febbraio 2023): 532. http://dx.doi.org/10.3390/biomedicines11020532.
Testo completoAbstract (sommario):
Mitochondrial diseases are a large class of human hereditary diseases, accompanied by the dysfunction of mitochondria and the disruption of cellular energy synthesis, that affect various tissues and organ systems. Mitochondrial DNA mutation-caused disorders are difficult to study because of the insufficient number of clinical cases and the challenges of creating appropriate models. There are many cellular models of mitochondrial diseases, but their application has a number of limitations. The most proper and promising models of mitochondrial diseases are animal models, which, unfortunately, are quite rare and more difficult to develop. The challenges mainly arise from the structural features of mitochondria, which complicate the genetic editing of mitochondrial DNA. This review is devoted to discussing animal models of human mitochondrial diseases and recently developed approaches used to create them. Furthermore, this review discusses mitochondrial diseases and studies of metabolic disorders caused by the mitochondrial DNA mutations underlying these diseases.
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Kučinskas, V. "Human mitochondrial DNA variation in Lithuania". Anthropologischer Anzeiger 52, n. 4 (13 dicembre 1994): 289–95. http://dx.doi.org/10.1127/anthranz/52/1994/289.
Testo completo
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Sharma, Nidhi, e T. Millo. "Mitochondrial DNA Typing for Forensic Identification". Journal of Forensic Chemistry and Toxicology 5, n. 1 (15 giugno 2019): 55–65. http://dx.doi.org/10.21088/jfct.2454.9363.5119.10.
Testo completoAbstract (sommario):
Mitochondrial DNA has more useful genetic information as compared to nucleic DNA because they are present in more number per cell. In decomposed or old biological samples nuclear material in the cell may not exist for a long period, so it is difficult to perform DNA analysis with the nuclear DNA from remains of biological samples. This high copy number in mtDNA increases the possibility of recovering sufficient DNA from compromised samples. For this reason, mtDNA can play an important role in the identification of missing person investigation, in mass disasters and other forensic investigations involving samples with limited biological material. Additionally, mtDNA is maternally inherited. Therefore, barring a mutation, an individual's mother, siblings, as well as all other maternally-related family members will have identical mtDNA sequences. As a result, forensic comparisons can be made using a reference sample from any maternal relative, even if the unknown and reference sample are separated by many generations. Anthropologically, mitochondrial DNA in the fossilised source is used to trace the human ancestry particularly of maternal lineage.
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Krishnan, Kim J., e Doug M. Turnbull. "Mitochondrial DNA and genetic disease". Essays in Biochemistry 47 (14 giugno 2010): 139–51. http://dx.doi.org/10.1042/bse0470139.
Testo completoAbstract (sommario):
From their very beginning to the present day, mitochondria have evolved to become a crucial organelle within the cell. The mitochondrial genome encodes only 37 genes, but its compact structure and minimal redundancy results in mutations on the mitochondrial genome being an important cause of genetic disease. In the present chapter we describe the up-to-date knowledge about mitochondrial DNA structure and function, and describe some of the consequences of defective function including disease and aging.
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Almannai, Mohammed, Ayman W. El-Hattab e Fernando Scaglia. "Mitochondrial DNA replication: clinical syndromes". Essays in Biochemistry 62, n. 3 (27 giugno 2018): 297–308. http://dx.doi.org/10.1042/ebc20170101.
Testo completoAbstract (sommario):
Each nucleated cell contains several hundreds of mitochondria, which are unique organelles in being under dual genome control. The mitochondria contain their own DNA, the mtDNA, but most of mitochondrial proteins are encoded by nuclear genes, including all the proteins required for replication, transcription, and repair of mtDNA. MtDNA replication is a continuous process that requires coordinated action of several enzymes that are part of the mtDNA replisome. It also requires constant supply of deoxyribonucleotide triphosphates(dNTPs) and interaction with other mitochondria for mixing and unifying the mitochondrial compartment. MtDNA maintenance defects are a growing list of disorders caused by defects in nuclear genes involved in different aspects of mtDNA replication. As a result of defects in these genes, mtDNA depletion and/or multiple mtDNA deletions develop in affected tissues resulting in variable manifestations that range from adult-onset mild disease to lethal presentation early in life.
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Qian, Wei, Namrata Kumar, Vera Roginskaya, Elise Fouquerel, Patricia L. Opresko, Sruti Shiva, Simon C. Watkins, Dmytro Kolodieznyi, Marcel P. Bruchez e Bennett Van Houten. "Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction". Proceedings of the National Academy of Sciences 116, n. 37 (26 agosto 2019): 18435–44. http://dx.doi.org/10.1073/pnas.1910574116.
Testo completoAbstract (sommario):
Reactive oxygen species (ROS) play important roles in aging, inflammation, and cancer. Mitochondria are an important source of ROS; however, the spatiotemporal ROS events underlying oxidative cellular damage from dysfunctional mitochondria remain unresolved. To this end, we have developed and validated a chemoptogenetic approach that uses a mitochondrially targeted fluorogen-activating peptide (Mito-FAP) to deliver a photosensitizer MG-2I dye exclusively to this organelle. Light-mediated activation (660 nm) of the Mito-FAP–MG-2I complex led to a rapid loss of mitochondrial respiration, decreased electron transport chain complex activity, and mitochondrial fragmentation. Importantly, one round of singlet oxygen produced a persistent secondary wave of mitochondrial superoxide and hydrogen peroxide lasting for over 48 h after the initial insult. By following ROS intermediates, we were able to detect hydrogen peroxide in the nucleus through ratiometric analysis of the oxidation of nuclear cysteine residues. Despite mitochondrial DNA (mtDNA) damage and nuclear oxidative stress induced by dysfunctional mitochondria, there was a lack of gross nuclear DNA strand breaks and apoptosis. Targeted telomere analysis revealed fragile telomeres and telomere loss as well as 53BP1-positive telomere dysfunction-induced foci (TIFs), indicating that DNA double-strand breaks occurred exclusively in telomeres as a direct consequence of mitochondrial dysfunction. These telomere defects activated ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair signaling. Furthermore, ATM inhibition exacerbated the Mito-FAP–induced mitochondrial dysfunction and sensitized cells to apoptotic cell death. This profound sensitivity of telomeres through hydrogen peroxide induced by dysregulated mitochondria reveals a crucial mechanism of telomere–mitochondria communication underlying the pathophysiological role of mitochondrial ROS in human diseases.
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Azbarova, A. V., e D. A. Knorre. "Role of mitochondrial DNA in yeast replicative aging". Биохимия 88, n. 12 (15 dicembre 2023): 2387–98. http://dx.doi.org/10.31857/s0320972523120047.
Testo completoAbstract (sommario):
Despite the variety of manifestations of aging, there are some common features and underlying mechanisms. In particular, mitochondria appears to be one of the most vulnerable systems in both metazoa and fungi. In this review, we discuss how mitochondrial dysfunction is related to replicative aging in the simplest eukaryotic model, the baker’s yeast Saccharomyces cerevisiae. We discuss a chain of events that starts from asymmetric inheritance of mitochondria by mother and daughter cells. With age, yeast mother cells start to experience a decrease in mitochondrial transmembrane potential and, consequently, a decrease in mitochondrial protein import efficiency. This induces mitochondrial protein precursors accumulation in the cytoplasm, the loss of mitochondrial DNA, and at the later stages - cell death. Interestingly, yeast strains without mitochondrial DNA can have both increased and increased lifespan compared to their counterparts with mtDNA. The direction of the effect depends on their ability to activate compensatory mechanisms preventing or mitigating negative consequences of mitochondrial dysfunction. The central role of mitochondria in yeast aging and death indicates that it is one of the most complex and, therefore, deregulation-prone systems in eukaryotic cells.
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Valdés-Aguayo, José J., Idalia Garza-Veloz, José I. Badillo-Almaráz, Sofia Bernal-Silva, Maria C. Martínez-Vázquez, Vladimir Juárez-Alcalá, José R. Vargas-Rodríguez et al. "Mitochondria and Mitochondrial DNA: Key Elements in the Pathogenesis and Exacerbation of the Inflammatory State Caused by COVID-19". Medicina 57, n. 9 (3 settembre 2021): 928. http://dx.doi.org/10.3390/medicina57090928.
Testo completoAbstract (sommario):
Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion’s membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.
20
Buneeva, Olga, Valerii Fedchenko, Arthur Kopylov e Alexei Medvedev. "Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA". Biomedicines 8, n. 12 (10 dicembre 2020): 591. http://dx.doi.org/10.3390/biomedicines8120591.
Testo completoAbstract (sommario):
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.
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Singh, Gyanesh, U. C. Pachouri, Devika Chanu Khaidem, Aman Kundu, Chirag Chopra e Pushplata Singh. "Mitochondrial DNA Damage and Diseases". F1000Research 4 (1 luglio 2015): 176. http://dx.doi.org/10.12688/f1000research.6665.1.
Testo completoAbstract (sommario):
Various endogenous and environmental factors can cause mitochondrial DNA (mtDNA) damage. One of the reasons for enhanced mtDNA damage could be its proximity to the source of oxidants, and lack of histone-like protective proteins. Moreover, mitochondria contain inadequate DNA repair pathways, and, diminished DNA repair capacity may be one of the factors responsible for high mutation frequency of the mtDNA. mtDNA damage might cause impaired mitochondrial function, and, unrepaired mtDNA damage has been frequently linked with several diseases. Exploration of mitochondrial perspective of diseases might lead to a better understanding of several diseases, and will certainly open new avenues for detection, cure, and prevention of ailments.
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Mustafa, Mohd Fazirul, Sharida Fakurazi, Maizaton Atmadini Abdullah e Sandra Maniam. "Pathogenic Mitochondria DNA Mutations: Current Detection Tools and Interventions". Genes 11, n. 2 (12 febbraio 2020): 192. http://dx.doi.org/10.3390/genes11020192.
Testo completoAbstract (sommario):
Mitochondria are best known for their role in energy production, and they are the only mammalian organelles that contain their own genomes. The mitochondrial genome mutation rate is reported to be 10–17 times higher compared to nuclear genomes as a result of oxidative damage caused by reactive oxygen species during oxidative phosphorylation. Pathogenic mitochondrial DNA mutations result in mitochondrial DNA disorders, which are among the most common inherited human diseases. Interventions of mitochondrial DNA disorders involve either the transfer of viable isolated mitochondria to recipient cells or genetically modifying the mitochondrial genome to improve therapeutic outcome. This review outlines the common mitochondrial DNA disorders and the key advances in the past decade necessary to improve the current knowledge on mitochondrial disease intervention. Although it is now 31 years since the first description of patients with pathogenic mitochondrial DNA was reported, the treatment for mitochondrial disease is often inadequate and mostly palliative. Advancements in diagnostic technology improved the molecular diagnosis of previously unresolved cases, and they provide new insight into the pathogenesis and genetic changes in mitochondrial DNA diseases.
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Peterson, Courtney M., Darcy L. Johannsen e Eric Ravussin. "Skeletal Muscle Mitochondria and Aging: A Review". Journal of Aging Research 2012 (2012): 1–20. http://dx.doi.org/10.1155/2012/194821.
Testo completoAbstract (sommario):
Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline.
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Nadalutti, Cristina A., Sylvette Ayala-Peña e Janine H. Santos. "Mitochondrial DNA damage as driver of cellular outcomes". American Journal of Physiology-Cell Physiology 322, n. 2 (1 febbraio 2022): C136—C150. http://dx.doi.org/10.1152/ajpcell.00389.2021.
Testo completoAbstract (sommario):
Mitochondria are primarily involved in energy production through the process of oxidative phosphorylation (OXPHOS). Increasing evidence has shown that mitochondrial function impacts a plethora of different cellular activities, including metabolism, epigenetics, and innate immunity. Like the nucleus, mitochondria own their genetic material, but this organellar genome is circular, present in multiple copies, and maternally inherited. The mitochondrial DNA (mtDNA) encodes 37 genes that are solely involved in OXPHOS. Maintenance of mtDNA, through replication and repair, requires the import of nuclear DNA-encoded proteins. Thus, mitochondria completely rely on the nucleus to prevent mitochondrial genetic alterations. As most cells contain hundreds to thousands of mitochondria, it follows that the shear number of organelles allows for the buffering of dysfunction—at least to some extent—before tissue homeostasis becomes impaired. Only red blood cells lack mitochondria entirely. Impaired mitochondrial function is a hallmark of aging and is involved in a number of different disorders, including neurodegenerative diseases, diabetes, cancer, and autoimmunity. Although alterations in mitochondrial processes unrelated to OXPHOS, such as fusion and fission, contribute to aging and disease, maintenance of mtDNA integrity is critical for proper organellar function. Here, we focus on how mtDNA damage contributes to cellular dysfunction and health outcomes.
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Menger, Katja E., Alejandro Rodríguez-Luis, James Chapman e Thomas J. Nicholls. "Controlling the topology of mammalian mitochondrial DNA". Open Biology 11, n. 9 (settembre 2021): 210168. http://dx.doi.org/10.1098/rsob.210168.
Testo completoAbstract (sommario):
The genome of mitochondria, called mtDNA, is a small circular DNA molecule present at thousands of copies per human cell. MtDNA is packaged into nucleoprotein complexes called nucleoids, and the density of mtDNA packaging affects mitochondrial gene expression. Genetic processes such as transcription, DNA replication and DNA packaging alter DNA topology, and these topological problems are solved by a family of enzymes called topoisomerases. Within mitochondria, topoisomerases are involved firstly in the regulation of mtDNA supercoiling and secondly in disentangling interlinked mtDNA molecules following mtDNA replication. The loss of mitochondrial topoisomerase activity leads to defects in mitochondrial function, and variants in the dual-localized type IA topoisomerase TOP3A have also been reported to cause human mitochondrial disease. We review the current knowledge on processes that alter mtDNA topology, how mtDNA topology is modulated by the action of topoisomerases, and the consequences of altered mtDNA topology for mitochondrial function and human health.
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Schäfer, Simon T., Lars Franken, Michael Adamzik, Beatrix Schumak, André Scherag, Andrea Engler, Niels Schönborn et al. "Mitochondrial DNA". Anesthesiology 124, n. 4 (1 aprile 2016): 923–33. http://dx.doi.org/10.1097/aln.0000000000001008.
Testo completoAbstract (sommario):
Abstract Background Critically ill patients are at high risk to suffer from sepsis, even in the absence of an initial infectious source, but the molecular mechanisms for their increased sepsis susceptibility, including a suppressed immune system, remain unclear. Although microbes and pathogen-associated molecular pattern are accepted inducers of sepsis and septic immunosuppression, the role of endogenous Toll-like receptor (TLR) ligands, such as mitochondrial DNA (mtDNA), in altering the immune response is unknown. Methods Mitochondrial DNA serum concentrations of the mitochondrial genes D-Loop and adenosine triphosphatase 6 were determined (quantitative polymerase chain reaction) in 165 septic patients and 50 healthy volunteers. Furthermore, cytotoxic T-cell activity was analyzed in wild-type and TLR9 knockout mice, with/without previous mtDNA administration, followed by injection of an ovalbumin-expressing adenoviral vector. Results Mitochondrial DNA serum concentrations were increased in septic patients (adenosine triphosphatase 6, 123-fold; D-Loop, 76-fold, P < 0.0001) compared with volunteers. Furthermore, a single mtDNA injection caused profound, TLR9-dependent immunosuppression of adaptive T-cell cytotoxicity in wild-type but not in TLR9 knockout mice and evoked various immunosuppressive mechanisms including the destruction of the splenic microstructure, deletion of cross-presenting dendritic cells, and up-regulation of programmed cell death ligand 1 and indoleamine 2,3-dioxygenase. Several of these findings in mice were mirrored in septic patients, and mtDNA concentrations were associated with an increased 30-day mortality. Conclusions The findings of this study imply that mtDNA, an endogenous danger associated molecular pattern, is a hitherto unknown inducer of septic immunoparalysis and one possible link between initial inflammation and subsequent immunosuppression in critically ill patients.
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Leijte, Guus Pieter, Peter Pickkers e Matthijs Kox. "Mitochondrial DNA". SHOCK 51, n. 2 (febbraio 2019): 266. http://dx.doi.org/10.1097/shk.0000000000001142.
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Jansen, Marcel P. B., Joris J. T. H. Roelofs e Jaklien C. Leemans. "Mitochondrial DNA". SHOCK 51, n. 2 (febbraio 2019): 267. http://dx.doi.org/10.1097/shk.0000000000001143.
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Yang, Xuan, Ruoyu Zhang, Kiichi Nakahira e Zhenglong Gu. "Mitochondrial DNA Mutation, Diseases, and Nutrient-Regulated Mitophagy". Annual Review of Nutrition 39, n. 1 (21 agosto 2019): 201–26. http://dx.doi.org/10.1146/annurev-nutr-082018-124643.
Testo completoAbstract (sommario):
A wide spectrum of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, have been shown to be associated with mitochondrial dysfunction through multiple molecular mechanisms. Mitochondria are particularly susceptible to nutrient deficiencies, and nutritional intervention is an essential way to maintain mitochondrial homeostasis. Recent advances in genetic manipulation and next-generation sequencing reveal the crucial roles of mitochondrial DNA (mtDNA) in various pathophysiological conditions. Mitophagy, a term coined to describe autophagy that targets dysfunctional mitochondria, has emerged as an important cellular process to maintain mitochondrial homeostasis and has been shown to be regulated by various nutrients and nutritional stresses. Given the high prevalence of mtDNA mutations in humans and their impact on mitochondrial function, it is important to investigate the mechanisms that regulate mtDNA mutation. Here, we discuss mitochondrial genetics and mtDNA mutations and their implications for human diseases. We also examine the role of mitophagy as a therapeutic target, highlighting how nutrients may eliminate mtDNA mutations through mitophagy.
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Chapman, James, Yi Shiau Ng e Thomas J. Nicholls. "The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes". Life 10, n. 9 (26 agosto 2020): 164. http://dx.doi.org/10.3390/life10090164.
Testo completoAbstract (sommario):
Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure.
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Manev, Hari, e Svetlana Dzitoyeva. "Progress in mitochondrial epigenetics". BioMolecular Concepts 4, n. 4 (1 agosto 2013): 381–89. http://dx.doi.org/10.1515/bmc-2013-0005.
Testo completoAbstract (sommario):
AbstractMitochondria, intracellular organelles with their own genome, have been shown capable of interacting with epigenetic mechanisms in at least four different ways. First, epigenetic mechanisms that regulate the expression of nuclear genome influence mitochondria by modulating the expression of nuclear-encoded mitochondrial genes. Second, a cell-specific mitochondrial DNA content (copy number) and mitochondrial activity determine the methylation pattern of nuclear genes. Third, mitochondrial DNA variants influence the nuclear gene expression patterns and the nuclear DNA (ncDNA) methylation levels. Fourth and most recent line of evidence indicates that mitochondrial DNA similar to ncDNA also is subject to epigenetic modifications, particularly by the 5-methylcytosine and 5-hydroxymethylcytosine marks. The latter interaction of mitochondria with epigenetics has been termed ‘mitochondrial epigenetics’. Here we summarize recent developments in this particular area of epigenetic research. Furthermore, we propose the term ‘mitoepigenetics’ to include all four above-noted types of interactions between mitochondria and epigenetics, and we suggest a more restricted usage of the term ‘mitochondrial epigenetics’ for molecular events dealing solely with the intra-mitochondrial epigenetics and the modifications of mitochondrial genome.
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Матіюк, В. В. "Diseases caused by mitochondrial DNA mutations". Вісник Полтавської державної аграрної академії, n. 4 (30 dicembre 2022): 86–92. http://dx.doi.org/10.31210/visnyk2022.04.10.
Testo completoAbstract (sommario):
This article highlights data on diseases caused by mitochondrial DNA mutations. The purpose of the review was to reveal existing diseases that arise as a result of mtDNA mutations. Mitochondrial diseases are diseases that are most often caused by genetically determined structural and functional disorders of mitochondria, and as a result, the energy supply of cells is disrupted. All mitochondrial diseases are transmitted through the maternal line, so if mutations are detected in time, they can be blocked and the further inheritance will be stopped. It is suggested that the role of mitochondrial DNA in certain diseases began to develop rapidly in 1988 when the first mutations in mitochondrial DNA were discovered. To understand the course and development of mitochondrial DNA, it is necessary to understand the structure and functional properties of the mitochondrial cell. MtDNA is a circular DNA molecule and is localized in mitochondria. Such organelles can replicate, transcribe, and translate their own DNA independently of nuclear DNA. Mitochondrial DNA can mutate more than 10 times more often than nuclear DNA. MtDNA has no protective functions against the phenomena of mutations. A mitochondrial cell can contain both mutant DNA and normal DNA. In genetics, such a condition is called heteroplasmy, which allows the survival of a lethal mutation. Single deletions, large deletions, and multiple deletions that are transmitted autosomally and have different phenotypic manifestations are the primary cause of the development of mitochondrial diseases. Scientists also identify systemic manifestations of mitochondrial DNA mutations. they include endocrine manifestations (diabetes), neurological diseases, gastrointestinal manifestations (acid-alkaline imbalance), and pulmonary manifestations (myoclonic epilepsy, hypoventilation abnormalities). Several main principles of treatment of mitochondropathies are distinguished: following a diet; additional introduction of cofactors involved in enzymatic reactions of energy metabolism (thiamine, riboflavin, nicotinamide, lipoic acid, biotin, carnitine); prescription of drugs, capable of carrying out the function of transferring electrons in the respiratory chain (vitamins K1 and K3, ascorbic acid).
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Silva, Sonia, Lola P. Camino e Andrés Aguilera. "Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability". Proceedings of the National Academy of Sciences 115, n. 43 (9 ottobre 2018): 11024–29. http://dx.doi.org/10.1073/pnas.1807258115.
Testo completoAbstract (sommario):
R loops are nucleic acid structures comprising an DNA–RNA hybrid and a displaced single-stranded DNA. These structures may occur transiently during transcription, playing essential biological functions. However, persistent R loops may become pathological as they are important drivers of genome instability and have been associated with human diseases. The mitochondrial degradosome is a functionally conserved complex from bacteria to human mitochondria. It is composed of the ATP-dependent RNA and DNA helicase SUV3 and the PNPase ribonuclease, playing a central role in mitochondrial RNA surveillance and degradation. Here we describe a new role for the mitochondrial degradosome in preventing the accumulation of pathological R loops in the mitochondrial DNA, in addition to preventing dsRNA accumulation. Our data indicate that, similar to the molecular mechanisms acting in the nucleus, RNA surveillance mechanisms in the mitochondria are crucial to maintain its genome integrity by counteracting pathological R-loop accumulation.
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Baysal, Bora. "Mitochondria: More than Mitochondrial DNA in Cancer". PLoS Medicine 3, n. 3 (28 marzo 2006): e156. http://dx.doi.org/10.1371/journal.pmed.0030156.
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KUROIWA, TSUNEYOSHI, MAKOTO FUJIE e HARUKO KUROIWA. "Studies on the Behavior of Mitochondrial DNA". Journal of Cell Science 101, n. 3 (1 marzo 1992): 483–93. http://dx.doi.org/10.1242/jcs.101.3.483.
Testo completoAbstract (sommario):
The fate of mitochondrial nuclei (known as nucleoids or mt-nuclei), which contain extremely small amounts of DNA, was followed in thin sections of the root meristem of Pelargonium zonale by embedding of samples in Technovit 7100 resin and double staining with 4′-6-diamidino-2-phenylindole (DAPI) and acridine orange, in combination with light-microscopic autoradiography and microphotometry. The synthesis of cell-nuclear DNA and cell division occurs actively in the root meristem, between 150 μm and 700 μm from the tip of the root. For simplicity, cells in S phase in the cortex were selected for main analysis as the model system for examination of cell proliferation. It is estimated, on the basis of the length of the cells in longitudinal median sections, that the cells in the cortex, which are generated in the area just above the quiescent center (QC) about 150 μm from the tip, enter the elongation zone after at least five divisions. In the entire cortex, individual cells in S phase have approximately 230 mitochondria that each contain one mt-nucleus. The observation suggests that individual mitochondria divide once per mitotic cycle in the entire region of the meristem. By contrast, on the basis of incorporation of [3H]thymidine into mt-nuclei, the synthesis of mitochondrial DNA (mtDNA) occurs independently of the mitotic cycle in a restricted region just above the QC. Fluorimetry, using a video-intensified microscope photon-counting system (VIMPICS), revealed that the mtDNA content per mt-nucleus in the cells just above QC, where the synthesis of mtDNA is active, corresponds to approximately 3000 kilobase pairs (kbp) but, in the meristematic cells just below the elongation zone of the root it falls to less than 170 kbp. These findings strongly suggest that the amount of mtDNA per mitochondrion which has been synthesized in the region just above the QC is reduced stepwise as a result of continuous divisions of mitochondria in the absence of the synthesis of mtDNA. This phenomenon would explain why differentiated cells with a large vacuole in the elongation zone have mitochondria that contain only extremely small amounts of mtDNA.
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Ghosh, Arijit, Sangheeta Bhattacharjee, Srijita Paul Chowdhuri, Abhik Mallick, Ishita Rehman, Sudipta Basu e Benu Brata Das. "SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy". Science Advances 5, n. 11 (novembre 2019): eaax9778. http://dx.doi.org/10.1126/sciadv.aax9778.
Testo completoAbstract (sommario):
A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 hydrolyzes the phosphodiester bond between DNA 3′-end and a tyrosyl moiety within trapped topoisomerase I (Top1)-DNA covalent complexes (Top1cc). TDP1 is critical for mitochondrial DNA (mtDNA) repair; however, the role of mitochondria remains largely unknown for the etiology of SCAN1. We demonstrate that mitochondria in cells expressing SCAN1-TDP1 (TDP1H493R) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1H493R-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1H493R-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1H493R prompts PTEN-induced kinase 1–dependent mitophagy to eliminate dysfunctional mitochondria. SCAN1-TDP1 in mitochondria creates a pathological state that allows neurons to turn on mitophagy to rescue fit mitochondria as a mechanism of survival.
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Lin, Yang-Hsiang, Siew-Na Lim, Cheng-Yi Chen, Hsiang-Cheng Chi, Chau-Ting Yeh e Wey-Ran Lin. "Functional Role of Mitochondrial DNA in Cancer Progression". International Journal of Molecular Sciences 23, n. 3 (31 gennaio 2022): 1659. http://dx.doi.org/10.3390/ijms23031659.
Testo completoAbstract (sommario):
Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.
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Podolak, Amira, Izabela Woclawek-Potocka e Krzysztof Lukaszuk. "The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?" Cells 11, n. 5 (24 febbraio 2022): 797. http://dx.doi.org/10.3390/cells11050797.
Testo completoAbstract (sommario):
Mitochondria are well known as ‘the powerhouses of the cell’. Indeed, their major role is cellular energy production driven by both mitochondrial and nuclear DNA. Such a feature makes these organelles essential for successful fertilisation and proper embryo implantation and development. Generally, mitochondrial DNA is exclusively maternally inherited; oocyte’s mitochondrial DNA level is crucial to provide sufficient ATP content for the developing embryo until the blastocyst stage of development. Additionally, human fertility and early embryogenesis may be affected by either point mutations or deletions in mitochondrial DNA. It was suggested that their accumulation may be associated with ovarian ageing. If so, is mitochondrial dysfunction the cause or consequence of ovarian ageing? Moreover, such an obvious relationship of mitochondria and mitochondrial genome with human fertility and early embryo development gives the field of mitochondrial research a great potential to be of use in clinical application. However, even now, the area of assessing and improving DNA quantity and function in reproductive medicine drives many questions and uncertainties. This review summarises the role of mitochondria and mitochondrial DNA in human reproduction and gives an insight into the utility of their clinical use.
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Lucini, Chantal B., e Ralf J. Braun. "Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies". Biomedicines 9, n. 4 (2 aprile 2021): 376. http://dx.doi.org/10.3390/biomedicines9040376.
Testo completoAbstract (sommario):
In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.
40
Yu, Chenxiao, Samieh Asadian e Marco Tigano. "Molecular and cellular consequences of mitochondrial DNA double-stranded breaks". Human Molecular Genetics 33, R1 (22 maggio 2024): R12—R18. http://dx.doi.org/10.1093/hmg/ddae048.
Testo completoAbstract (sommario):
Abstract Mitochondria are subcellular organelles essential for life. Beyond their role in producing energy, mitochondria govern various physiological mechanisms, encompassing energy generation, metabolic processes, apoptotic events, and immune responses. Mitochondria also contain genetic material that is susceptible to various forms of damage. Mitochondrial double-stranded breaks (DSB) are toxic lesions that the nucleus repairs promptly. Nevertheless, the significance of DSB repair in mammalian mitochondria is controversial. This review presents an updated view of the available research on the consequences of mitochondrial DNA DSB from the molecular to the cellular level. We discuss the crucial function of mitochondrial DNA damage in regulating processes such as senescence, integrated stress response, and innate immunity. Lastly, we discuss the potential role of mitochondrial DNA DSB in mediating the cellular consequences of ionizing radiations, the standard of care in treating solid tumors.
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Wang, Jie, Fei Lin, Li-li Guo, Xing-jiang Xiong e Xun Fan. "Cardiovascular Disease, Mitochondria, and Traditional Chinese Medicine". Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/143145.
Testo completoAbstract (sommario):
Recent studies demonstrated that mitochondria play an important role in the cardiovascular system and mutations of mitochondrial DNA affect coronary artery disease, resulting in hypertension, atherosclerosis, and cardiomyopathy. Traditional Chinese medicine (TCM) has been used for thousands of years to treat cardiovascular disease, but it is not yet clear how TCM affects mitochondrial function. By reviewing the interactions between the cardiovascular system, mitochondrial DNA, and TCM, we show that cardiovascular disease is negatively affected by mutations in mitochondrial DNA and that TCM can be used to treat cardiovascular disease by regulating the structure and function of mitochondria via increases in mitochondrial electron transport and oxidative phosphorylation, modulation of mitochondrial-mediated apoptosis, and decreases in mitochondrial ROS. However further research is still required to identify the mechanism by which TCM affects CVD and modifies mitochondrial DNA.
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Faria, Rúben, Milan Paul, Swati Biswas, Eric Vivès, Prisca Boisguérin, Ângela Sousa e Diana Costa. "Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy". Pharmaceutics 14, n. 4 (31 marzo 2022): 757. http://dx.doi.org/10.3390/pharmaceutics14040757.
Testo completoAbstract (sommario):
Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine–dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation.
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Kondadi, Arun Kumar, Ruchika Anand e Andreas S. Reichert. "Functional Interplay between Cristae Biogenesis, Mitochondrial Dynamics and Mitochondrial DNA Integrity". International Journal of Molecular Sciences 20, n. 17 (3 settembre 2019): 4311. http://dx.doi.org/10.3390/ijms20174311.
Testo completoAbstract (sommario):
Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly changed over the past few decades as many studies have revealed a remarkable dynamicity of mitochondrial shapes and sizes both at the cellular and intra-mitochondrial levels. Aberrant changes in mitochondrial dynamics and cristae structure are associated with ageing and numerous human diseases (e.g., cancer, diabetes, various neurodegenerative diseases, types of neuro- and myopathies). Another unique feature of mitochondria is that they harbor their own genome, the mitochondrial DNA (mtDNA). MtDNA exists in several hundreds to thousands of copies per cell and is arranged and packaged in the mitochondrial matrix in structures termed mt-nucleoids. Many human diseases are mechanistically linked to mitochondrial dysfunction and alteration of the number and/or the integrity of mtDNA. In particular, several recent studies identified remarkable and partly unexpected links between mitochondrial structure, fusion and fission dynamics, and mtDNA. In this review, we will provide an overview about these recent insights and aim to clarify how mitochondrial dynamics, cristae ultrastructure and mtDNA structure influence each other and determine mitochondrial functions.
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Leão Barros, Mariceli Baia, Danilo do Rosário Pinheiro e Bárbara do Nascimento Borges. "Mitochondrial DNA Alterations in Glioblastoma (GBM)". International Journal of Molecular Sciences 22, n. 11 (29 maggio 2021): 5855. http://dx.doi.org/10.3390/ijms22115855.
Testo completoAbstract (sommario):
Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.
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Zheng, Ningning, Dan Wei, Bo Dai, Lanyan Zheng, Mingyi Zhao, Na Xin, Zhihong Chi et al. "Mitochondrial Genome Encoded Proteins Expression Disorder, the Possible Mechanism of the Heart Disease in Metabolic Syndrome". Cellular Physiology and Biochemistry 43, n. 3 (2017): 959–68. http://dx.doi.org/10.1159/000481649.
Testo completoAbstract (sommario):
Background/Aims: The direct consequence of metabolic syndrome (MS) is the increased morbidity and mortality caused by the heart disease. We tried to explain why the heart is more severely damaged during MS from the point of mitochondria, the center of cellular metabolism. Methods: 1. The classic diet induced MS rat model was used to observe the morphological changes of mitochondria by transmission electron microscope (TEM); 2. The expression of mitochondrial DNA (mt-DNA) encoded proteins was observed by immunohistochemistry and Western blot; 3. The expression of mitochondrial ribosomal proteins (MRPs) was observed by real-time PCR. Results: 1. The mitochondrial volume increased but the number was normal in myocardial cells of the MS rats. But in the hepatocytes and skeletal muscle cells, the mitochondrial number decreased; 2.The mt-DNA encoded protein cytochrome b increased significantly in heart but decreased in liver and the ATPase6 increased in liver but decreased in heart of the MS rats; 3. The mRNA levels of MRPS23, MRPL27, MRPL45 and MRPL48 elevated in heart but down-regulated in liver of the MS rats. Conclusion: The morphologic and functional alterations of mitochondrion in MS were tissue specific. Heart displays a distinctive pattern of mitochondrial metabolic status compared with other tissues.
46
Brieba. "Structure–Function Analysis Reveals the Singularity of Plant Mitochondrial DNA Replication Components: A Mosaic and Redundant System". Plants 8, n. 12 (21 novembre 2019): 533. http://dx.doi.org/10.3390/plants8120533.
Testo completoAbstract (sommario):
Plants are sessile organisms, and their DNA is particularly exposed to damaging agents. The integrity of plant mitochondrial and plastid genomes is necessary for cell survival. During evolution, plants have evolved mechanisms to replicate their mitochondrial genomes while minimizing the effects of DNA damaging agents. The recombinogenic character of plant mitochondrial DNA, absence of defined origins of replication, and its linear structure suggest that mitochondrial DNA replication is achieved by a recombination-dependent replication mechanism. Here, I review the mitochondrial proteins possibly involved in mitochondrial DNA replication from a structural point of view. A revision of these proteins supports the idea that mitochondrial DNA replication could be replicated by several processes. The analysis indicates that DNA replication in plant mitochondria could be achieved by a recombination-dependent replication mechanism, but also by a replisome in which primers are synthesized by three different enzymes: Mitochondrial RNA polymerase, Primase-Helicase, and Primase-Polymerase. The recombination-dependent replication model and primers synthesized by the Primase-Polymerase may be responsible for the presence of genomic rearrangements in plant mitochondria.
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Tamar Giorgadze, Tamar Giorgadze, e Sofia Giorgadze Sofia Giorgadze. "MITOCHONDRIA – AS A TARGET OF ENVIRONMENTAL FACTORS". Socio World-Social Research & Behavioral Sciences 12, n. 02 (25 dicembre 2023): 44–49. http://dx.doi.org/10.36962/swd12022023-44.
Testo completoAbstract (sommario):
Mitochondria—tiny organelles in the cell that each possess their own DNA—have come under a growing scientific spotlight. The traditional view of mitochondria as static organelles has been reassessed. Scientists increasingly believe they play a central role in many, if not most, human illnesses. Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells, tissues, and organs. The purpose of this review is to discuss the mechanism and consequences of mitochondrial dysfunction caused by environmental factors. Recognition of the key role of mtDNA integrity and mitochondrial function in health has grown greatly in recent years. The environment can influence human health and disease in many harmful ways. One such mechanism for this is through environmental factors increasing oxidative stress in the cell, and this stress can subsequently lead to alterations in DNA molecule. Research shows that mitochondrial DNA is uniquely susceptible to the damaging effects of reactive oxygen species (ROS). These effects are more extensive and longer-lasting in mitochondrial DNA than they are in the nuclear genome. In humans, the most concerning chemicals may be mitochondrial toxins with long half-lives. Examples include lipophilic chemical mixtures such as persistent organic pollutants (POPs) and heavy metals. Other examples of chronic exposure to mitochondrial toxins are air pollution and cigarette smoking. Compared with its nuclear counterpart, mitochondrial DNA generally has less capacity to repair itself. It specifically can’t delete the large DNA helix–distorting adducts formed when mitochondrial DNA bases are damaged by mutagens such as polyaromatic hydrocarbons and ultraviolet radiation. Conclusion - Despite numerous existing researches, the specified question requires further study. it is necessary clearer understanding of what specific environmental factors damage mitochondria and how they do so, this is important way to prevent many diseases induced by mitochondrial dysfunction. Keywords: Mitochondria; Environmental Factors; Mitochondrial dysfunction;
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Shen, Liang, e Xianquan Zhan. "Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer". Oxidative Medicine and Cellular Longevity 2022 (20 aprile 2022): 1–22. http://dx.doi.org/10.1155/2022/5634724.
Testo completoAbstract (sommario):
The mitochondrion is a very versatile organelle that participates in some important cancer-associated biological processes, including energy metabolism, oxidative stress, mitochondrial DNA (mtDNA) mutation, cell apoptosis, mitochondria-nuclear communication, dynamics, autophagy, calcium overload, immunity, and drug resistance in ovarian cancer. Multiomics studies have found that mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways act in human ovarian cancer, which demonstrates that mitochondria play critical roles in ovarian cancer. Many molecular targeted drugs have been developed against mitochondrial dysfunction pathways in ovarian cancer, including olive leaf extract, nilotinib, salinomycin, Sambucus nigra agglutinin, tigecycline, and eupatilin. This review article focuses on the underlying biological roles of mitochondrial dysfunction in ovarian cancer progression based on omics data, potential molecular relationship between mitochondrial dysfunction and oxidative stress, and future perspectives of promising biomarkers and therapeutic targets based on the mitochondrial dysfunction pathway for ovarian cancer.
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Knorre, Dmitry A. "Intracellular quality control of mitochondrial DNA: evidence and limitations". Philosophical Transactions of the Royal Society B: Biological Sciences 375, n. 1790 (2 dicembre 2019): 20190176. http://dx.doi.org/10.1098/rstb.2019.0176.
Testo completoAbstract (sommario):
Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent ‘leakage’ of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue ‘Linking the mitochondrial genotype to phenotype: a complex endeavour’.
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Chen, Dexi, Manabu Minami, David C. Henshall, Robert Meller, Glen Kisby e Roger P. Simon. "Upregulation of Mitochondrial Base-Excision Repair Capability within Rat Brain after Brief Ischemia". Journal of Cerebral Blood Flow & Metabolism 23, n. 1 (gennaio 2003): 88–98. http://dx.doi.org/10.1097/01.wcb.0000039286.37737.19.
Testo completoAbstract (sommario):
The mechanism by which brief episodes of cerebral ischemia confer protection (tolerance) against subsequent prolonged ischemic challenges remains unclear, but may involve upregulation of cell injury repair capability. The mitochondrion is a key site for the regulation of cell death pathways, and damage to mitochondrial genes has been linked to a number of neurologic diseases and aging. Therefore, the authors examined the response of the DNA base excision repair (BER) pathway in rat brain mitochondria after either brief (tolerance-inducing) or prolonged (injury-producing) focal cerebral ischemia. Brief (30-minute) middle cerebral artery occlusion (MCAO) induced mild oxidative mitochondrial DNA damage and initiated a prolonged (up to 72-hour) activation above control levels of the principal enzymes of the mitochondrial BER pathway, including uracil DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase-γ, and DNA ligase. In contrast, prolonged (100-minute MCAO) ischemia induced more substantial mitochondrial oxidative DNA damage whereas elevation of BER activity was transient (∼1 hour), declining to less than control levels over the course of 4 to 72 hours. These data reveal the differences in BER capacity after brief or prolonged ischemia, which may contribute to the neuron's ability to resist subsequent ischemic insults.