Journal articles: 'Mitochondrial DNA replication'

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Almannai, Mohammed, Ayman W. El-Hattab, and Fernando Scaglia. "Mitochondrial DNA replication: clinical syndromes." Essays in Biochemistry 62, no. 3 (June 27, 2018): 297–308. http://dx.doi.org/10.1042/ebc20170101.

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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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Brieba. "Structure–Function Analysis Reveals the Singularity of Plant Mitochondrial DNA Replication Components: A Mosaic and Redundant System." Plants 8, no. 12 (November 21, 2019): 533. http://dx.doi.org/10.3390/plants8120533.

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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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Bradshaw, Patrick C., and David C. Samuels. "A computational model of mitochondrial deoxynucleotide metabolism and DNA replication." American Journal of Physiology-Cell Physiology 288, no. 5 (May 2005): C989—C1002. http://dx.doi.org/10.1152/ajpcell.00530.2004.

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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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Falkenberg, Maria. "Mitochondrial DNA replication in mammalian cells: overview of the pathway." Essays in Biochemistry 62, no. 3 (June 7, 2018): 287–96. http://dx.doi.org/10.1042/ebc20170100.

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Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome and a dedicated DNA replication machinery is required for its maintenance. Many disease-causing mutations affect mitochondrial replication factors and a detailed understanding of the replication process may help to explain the pathogenic mechanisms underlying a number of mitochondrial diseases. We here give a brief overview of DNA replication in mammalian mitochondria, describing our current understanding of this process and some unanswered questions remaining.

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Meeusen, Shelly, and Jodi Nunnari. "Evidence for a two membrane–spanning autonomous mitochondrial DNA replisome." Journal of Cell Biology 163, no. 3 (November 3, 2003): 503–10. http://dx.doi.org/10.1083/jcb.200304040.

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The unit of inheritance for mitochondrial DNA (mtDNA) is a complex nucleoprotein structure termed the nucleoid. The organization of the nucleoid as well as its role in mtDNA replication remain largely unknown. Here, we show in Saccharomyces cerevisiae that at least two populations of nucleoids exist within the same mitochondrion and can be distinguished by their association with a discrete proteinaceous structure that spans the outer and inner mitochondrial membranes. Surprisingly, this two membrane–spanning structure (TMS) persists and self-replicates in the absence of mtDNA. We tested whether TMS functions to direct the replication of mtDNA. By monitoring BrdU incorporation, we observed that actively replicating nucleoids are associated exclusively with TMS. Consistent with TMS's role in mtDNA replication, we found that Mip1, the mtDNA polymerase, is also a stable component of TMS. Taken together, our observations reveal the existence of an autonomous two membrane–spanning mitochondrial replisome as well as provide a mechanism for how mtDNA replication and inheritance may be physically linked.

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Bailey, Laura J., and Aidan J. Doherty. "Mitochondrial DNA replication: a PrimPol perspective." Biochemical Society Transactions 45, no. 2 (April 13, 2017): 513–29. http://dx.doi.org/10.1042/bst20160162.

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PrimPol, (primase–polymerase), the most recently identified eukaryotic polymerase, has roles in both nuclear and mitochondrial DNA maintenance. PrimPol is capable of acting as a DNA polymerase, with the ability to extend primers and also bypass a variety of oxidative and photolesions. In addition, PrimPol also functions as a primase, catalysing the preferential formation of DNA primers in a zinc finger-dependent manner. Although PrimPol's catalytic activities have been uncovered in vitro, we still know little about how and why it is targeted to the mitochondrion and what its key roles are in the maintenance of this multicopy DNA molecule. Unlike nuclear DNA, the mammalian mitochondrial genome is circular and the organelle has many unique proteins essential for its maintenance, presenting a differing environment within which PrimPol must function. Here, we discuss what is currently known about the mechanisms of DNA replication in the mitochondrion, the proteins that carry out these processes and how PrimPol is likely to be involved in assisting this vital cellular process.

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Holt, I. J., and A. Reyes. "Human Mitochondrial DNA Replication." Cold Spring Harbor Perspectives in Biology 4, no. 12 (November 9, 2012): a012971. http://dx.doi.org/10.1101/cshperspect.a012971.

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Billard, Pauline, and Delphine A. Poncet. "Replication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing." International Journal of Molecular Sciences 20, no. 19 (October 8, 2019): 4959. http://dx.doi.org/10.3390/ijms20194959.

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Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2β, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.

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Holmes, J. Bradley, Gokhan Akman, Stuart R. Wood, Kiran Sakhuja, Susana M. Cerritelli, Chloe Moss, Mark R. Bowmaker, Howard T. Jacobs, Robert J. Crouch, and Ian J. Holt. "Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication." Proceedings of the National Academy of Sciences 112, no. 30 (July 10, 2015): 9334–39. http://dx.doi.org/10.1073/pnas.1503653112.

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Encoding ribonuclease H1 (RNase H1) degrades RNA hybridized to DNA, and its function is essential for mitochondrial DNA maintenance in the developing mouse. Here we define the role of RNase H1 in mitochondrial DNA replication. Analysis of replicating mitochondrial DNA in embryonic fibroblasts lacking RNase H1 reveals retention of three primers in the major noncoding region (NCR) and one at the prominent lagging-strand initiation site termed Ori-L. Primer retention does not lead immediately to depletion, as the persistent RNA is fully incorporated in mitochondrial DNA. However, the retained primers present an obstacle to the mitochondrial DNA polymerase γ in subsequent rounds of replication and lead to the catastrophic generation of a double-strand break at the origin when the resulting gapped molecules are copied. Hence, the essential role of RNase H1 in mitochondrial DNA replication is the removal of primers at the origin of replication.

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Menger, Katja E., Alejandro Rodríguez-Luis, James Chapman, and Thomas J. Nicholls. "Controlling the topology of mammalian mitochondrial DNA." Open Biology 11, no. 9 (September 2021): 210168. http://dx.doi.org/10.1098/rsob.210168.

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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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Pinter, Stefan F., Sarah D. Aubert, and Virginia A. Zakian. "The Schizosaccharomyces pombe Pfh1p DNA Helicase Is Essential for the Maintenance of Nuclear and Mitochondrial DNA." Molecular and Cellular Biology 28, no. 21 (August 25, 2008): 6594–608. http://dx.doi.org/10.1128/mcb.00191-08.

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ABSTRACT Schizosaccharomyces pombe Pfh1p is an essential member of the Pif family of 5′-3′ DNA helicases. The two Saccharomyces cerevisiae homologs, Pif1p and Rrm3p, function in nuclear DNA replication, telomere length regulation, and mitochondrial genome integrity. We demonstrate here the existence of multiple Pfh1p isoforms that localized to either nuclei or mitochondria. The catalytic activity of Pfh1p was essential in both cellular compartments. The absence of nuclear Pfh1p resulted in G2 arrest and accumulation of DNA damage foci, a finding suggestive of an essential role in DNA replication. Exogenous DNA damage resulted in localization of Pfh1p to DNA damage foci, suggesting that nuclear Pfh1p also functions in DNA repair. The absence of mitochondrial Pfh1p caused rapid depletion of mitochondrial DNA. Despite localization to nuclei and mitochondria in S. pombe, neither of the S. cerevisiae homologs, nor human PIF1, suppressed the lethality of pfh1Δ cells. However, the essential nuclear function of Pfh1p could be supplied by Rrm3p. Expression of Rrm3p suppressed the accumulation of DNA damage foci but not the hydroxyurea sensitivity of cells depleted of nuclear Pfh1p. Together, these data demonstrate that Pfh1p has essential roles in the replication of both nuclear and mitochondrial DNA.

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Xu, Dongyang, Lingcong Luo, Yu Huang, Meng Lu, Lu Tang, Yong Diao, and Philipp Kapranov. "Dynamic Patterns of Mammalian Mitochondrial DNA Replication Uncovered Using SSiNGLe-5′ES." International Journal of Molecular Sciences 24, no. 11 (June 3, 2023): 9711. http://dx.doi.org/10.3390/ijms24119711.

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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.

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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, no. 9 (September 3, 2021): 928. http://dx.doi.org/10.3390/medicina57090928.

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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.

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Nomiyama, Tomoko, Daiki Setoyama, Takehiro Yasukawa, and Dongchon Kang. "Mitochondria metabolomics reveals a role of β-nicotinamide mononucleotide metabolism in mitochondrial DNA replication." Journal of Biochemistry 171, no. 3 (December 4, 2021): 325–38. http://dx.doi.org/10.1093/jb/mvab136.

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Abstract Mitochondrial DNA (mtDNA) replication is tightly regulated and necessary for cellular homeostasis; however, its relationship with mitochondrial metabolism remains unclear. Advances in metabolomics integrated with the rapid isolation of mitochondria will allow for remarkable progress in analyzing mitochondrial metabolism. Here, we propose a novel methodology for mitochondria-targeted metabolomics, which employs a quick isolation procedure using a hemolytic toxin from Streptococcus pyogenes streptolysin O (SLO). SLO isolation of mitochondria from cultured HEK293 cells is time- and labor-saving for simultaneous multi-sample processing and has been applied to various other cell lines in this study. Furthermore, our method can detect the time-dependent reduction in mitochondrial ATP in response to a glycolytic inhibitor 2-deoxyglucose, indicating the suitability to prepare metabolite analysis–competent mitochondria. Using this methodology, we searched for specific mitochondrial metabolites associated with mtDNA replication activation, and nucleotides and NAD+ were identified to be prominently altered. Most notably, treatment of β-nicotinamide mononucleotide (β-NMN), a precursor of NAD+, to HEK293 cells activated and improved the rate of mtDNA replication by increasing nucleotides in mitochondria and decreasing their degradation products: nucleosides. Our results suggest that β-NMN metabolism plays a role in supporting mtDNA replication by maintaining the nucleotide pool balance in the mitochondria.

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Sullivan, Eric D., Matthew J. Longley, and William C. Copeland. "Polymerase γ efficiently replicates through many natural template barriers but stalls at the HSP1 quadruplex." Journal of Biological Chemistry 295, no. 51 (October 19, 2020): 17802–15. http://dx.doi.org/10.1074/jbc.ra120.015390.

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Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we identified a specific G-quadruplex–forming sequence at the heavy-strand promoter (HSP1) that has the potential to cause significant stalling of mtDNA replication. Furthermore, this structured region of DNA corresponds to the break site for a large (3,895 bp) deletion observed in mitochondrial disease patients. The presence of this deletion in humans correlates with UV exposure, and we have found that efficiency of polymerase γ DNA synthesis is reduced after this quadruplex is exposed to UV in vitro.

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Copeland, William C. "Defects of Mitochondrial DNA Replication." Journal of Child Neurology 29, no. 9 (June 30, 2014): 1216–24. http://dx.doi.org/10.1177/0883073814537380.

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Bruhn, David F., Mark P. Sammartino, and Michele M. Klingbeil. "Three Mitochondrial DNA Polymerases Are Essential for Kinetoplast DNA Replication and Survival of Bloodstream Form Trypanosoma brucei." Eukaryotic Cell 10, no. 6 (April 29, 2011): 734–43. http://dx.doi.org/10.1128/ec.05008-11.

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ABSTRACT Trypanosoma brucei , the causative agent of human African trypanosomiasis, has a complex life cycle that includes multiple life cycle stages and metabolic changes as the parasite switches between insect vector and mammalian host. The parasite's single mitochondrion contains a unique catenated mitochondrial DNA network called kinetoplast DNA (kDNA) that is composed of minicircles and maxicircles. Long-standing uncertainty about the requirement of kDNA in bloodstream form (BF) T. brucei has recently eroded, with reports of posttranscriptional editing and subsequent translation of kDNA-encoded transcripts as essential processes for BF parasites. These studies suggest that kDNA and its faithful replication are indispensable for this life cycle stage. Here we demonstrate that three kDNA replication proteins (mitochondrial DNA polymerases IB, IC, and ID) are required for BF parasite viability. Silencing of each polymerase was lethal, resulting in kDNA loss, persistence of prereplication DNA monomers, and collapse of the mitochondrial membrane potential. These data demonstrate that kDNA replication is indeed crucial for BF T. brucei . The contributions of mitochondrial DNA polymerases IB, IC, and ID to BF parasite viability suggest that these and other kDNA replication proteins warrant further investigation as a new class of targets for the development of antitrypanosomal drugs.

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Bodnar, A. G., J. M. Cooper, J. V. Leonard, and A. H. V. Schapira. "Respiratory-deficient human fibroblasts exhibiting defective mitochondrial DNA replication." Biochemical Journal 305, no. 3 (February 1, 1995): 817–22. http://dx.doi.org/10.1042/bj3050817.

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We have characterized cultured skin fibroblasts from two siblings affected with a fatal mitochondrial disease caused by a nuclear genetic defect. Mitochondrial respiratory-chain function was severely decreased in these cells. Southern-blot analysis showed that the fibroblasts had reduced levels of mitochondrial DNA (mtDNA). The mtDNA was unstable and was eliminated from the cultured cells over many generations, generating the rho0 genotype. As the mtDNA level decreased, the cells became more dependent upon pyruvate and uridine for growth. Nuclear-encoded subunits of respiratory-chain complexes were synthesized and imported into the mitochondria of the mtDNA-depleted cells, albeit at reduced levels compared with the controls. Mitochondrial protein synthesis directed by the residual mtDNA indicated that the mtDNA was expressed and that the defect specifically involves the replication or maintenance of mtDNA. This is a unique example of a respiratory-deficient human cell line exhibiting defective mtDNA replication.

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Jiang, Min, Xie Xie, Xuefeng Zhu, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, et al. "The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication." Science Advances 7, no. 27 (July 2021): eabf8631. http://dx.doi.org/10.1126/sciadv.abf8631.

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We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication.

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Hood, Wendy R., Ashley S. Williams, and Geoffrey E. Hill. "An Ecologist’s Guide to Mitochondrial DNA Mutations and Senescence." Integrative and Comparative Biology 59, no. 4 (June 5, 2019): 970–82. http://dx.doi.org/10.1093/icb/icz097.

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Abstract Longevity plays a key role in the fitness of organisms, so understanding the processes that underlie variance in senescence has long been a focus of ecologists and evolutionary biologists. For decades, the performance and ultimate decline of mitochondria have been implicated in the demise of somatic tissue, but exactly why mitochondrial function declines as individual’s age has remained elusive. A possible source of decline that has been of intense debate is mutations to the mitochondrial DNA. There are two primary sources of such mutations: oxidative damage, which is widely discussed by ecologists interested in aging, and mitochondrial replication error, which is less familiar to most ecologists. The goal of this review is to introduce ecologists and evolutionary biologists to the concept of mitochondrial replication error and to review the current status of research on the relative importance of replication error in senescence. We conclude by detailing some of the gaps in our knowledge that currently make it difficult to deduce the relative importance of replication error in wild populations and encourage organismal biologists to consider this variable both when interpreting their results and as viable measure to include in their studies.

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Concepción-Acevedo, Jeniffer, Juemin Luo, and Michele M. Klingbeil. "Dynamic Localization of Trypanosoma brucei Mitochondrial DNA Polymerase ID." Eukaryotic Cell 11, no. 7 (January 27, 2012): 844–55. http://dx.doi.org/10.1128/ec.05291-11.

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ABSTRACT Trypanosomes contain a unique form of mitochondrial DNA called kinetoplast DNA (kDNA) that is a catenated network composed of minicircles and maxicircles. Several proteins are essential for network replication, and most of these localize to the antipodal sites or the kinetoflagellar zone. Essential components for kDNA synthesis include three mitochondrial DNA polymerases TbPOLIB, TbPOLIC, and TbPOLID). In contrast to other kDNA replication proteins, TbPOLID was previously reported to localize throughout the mitochondrial matrix. This spatial distribution suggests that TbPOLID requires redistribution to engage in kDNA replication. Here, we characterize the subcellular distribution of TbPOLID with respect to the Trypanosoma brucei cell cycle using immunofluorescence microscopy. Our analyses demonstrate that in addition to the previously reported matrix localization, TbPOLID was detected as discrete foci near the kDNA. TbPOLID foci colocalized with replicating minicircles at antipodal sites in a specific subset of the cells during stages II and III of kDNA replication. Additionally, the TbPOLID foci were stable following the inhibition of protein synthesis, detergent extraction, and DNase treatment. Taken together, these data demonstrate that TbPOLID has a dynamic localization that allows it to be spatially and temporally available to perform its role in kDNA replication.

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Liu, Pingfang, Limin Qian, Jung-Suk Sung, Nadja C. de Souza-Pinto, Li Zheng, Daniel F. Bogenhagen, Vilhelm A. Bohr, David M. Wilson, Binghui Shen, and Bruce Demple. "Removal of Oxidative DNA Damage via FEN1-Dependent Long-Patch Base Excision Repair in Human Cell Mitochondria." Molecular and Cellular Biology 28, no. 16 (June 9, 2008): 4975–87. http://dx.doi.org/10.1128/mcb.00457-08.

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ABSTRACT Repair of oxidative DNA damage in mitochondria was thought limited to short-patch base excision repair (SP-BER) replacing a single nucleotide. However, certain oxidative lesions cannot be processed by SP-BER. Here we report that 2-deoxyribonolactone (dL), a major type of oxidized abasic site, inhibits replication by mitochondrial DNA (mtDNA) polymerase γ and interferes with SP-BER by covalently trapping polymerase γ during attempted dL excision. However, repair of dL was detected in human mitochondrial extracts, and we show that this repair is via long-patch BER (LP-BER) dependent on flap endonuclease 1 (FEN1), not previously known to be present in mitochondria. FEN1 was retained in protease-treated mitochondria and detected in mitochondrial nucleoids that contain known mitochondrial replication and transcription proteins. Results of immunofluorescence and subcellular fractionation studies were also consistent with the presence of FEN1 in the mitochondria of intact cells. Immunodepletion experiments showed that the LP-BER activity of mitochondrial extracts was strongly diminished in parallel with the removal of FEN1, although some activity remained, suggesting the presence of an additional flap-removing enzyme. Biological evidence for a FEN1 role in repairing mitochondrial oxidative DNA damage was provided by RNA interference experiments, with the extent of damage greater and the recovery slower in FEN1-depleted cells than in control cells. The mitochondrial LP-BER pathway likely plays important roles in repairing dL lesions and other oxidative lesions and perhaps in normal mtDNA replication.

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Peter, Bradley, and Maria Falkenberg. "TWINKLE and Other Human Mitochondrial DNA Helicases: Structure, Function and Disease." Genes 11, no. 4 (April 9, 2020): 408. http://dx.doi.org/10.3390/genes11040408.

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Mammalian mitochondria contain a circular genome (mtDNA) which encodes subunits of the oxidative phosphorylation machinery. The replication and maintenance of mtDNA is carried out by a set of nuclear-encoded factors—of which, helicases form an important group. The TWINKLE helicase is the main helicase in mitochondria and is the only helicase required for mtDNA replication. Mutations in TWINKLE cause a number of human disorders associated with mitochondrial dysfunction, neurodegeneration and premature ageing. In addition, a number of other helicases with a putative role in mitochondria have been identified. In this review, we discuss our current knowledge of TWINKLE structure and function and its role in diseases of mtDNA maintenance. We also briefly discuss other potential mitochondrial helicases and postulate on their role(s) in mitochondria.

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Meirelles, Flávio V., and Lawrence C. Smith. "Mitochondrial Genotype Segregation During Preimplantation Development in Mouse Heteroplasmic Embryos." Genetics 148, no. 2 (February 1, 1998): 877–83. http://dx.doi.org/10.1093/genetics/148.2.877.

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Abstract Mitochondrial DNA content remains constant between the mature egg and the blastocyst stage in mammals, making this the only period in development when genotypes segregate to daughter cells without the confounding effect of genotype replication. To analyze the segregation patterns of mitochondrial DNA during preimplantation development, we introduced polymorphic mitochondria either peripherally (cytoplast transplantation) or in the perinuclear vicinity (karyplast transplantation) into zygotes. Genotype ratios were significantly more variable among blastomeres from cytoplast (coefficient of variation = 83.8%) than karyoplast (coefficient of variation = 34.7%) reconstructed zygotes. These results suggest that heteroplasmy caused by polymorphic mitochondria positioned in the periphery of oocytes at the time of fertilization shows a more stringent segregation pattern than when the organelle is in the vicinity of the nucleus. Moreover, donor-to-host mitochondrial genotype ratios in karyoplast-derived groups increased significantly during development, particularly in the C57BL/6 group, where the ratio practically doubled between the four-cell (17.3%) and the blastocyst stage (29.6%). Although the mechanisms controlling this preferential replication of nuclear-type mitochondrial DNA are unknown, it is suggested that access to nuclear-derived transcription and replication factors could lead to the preferential replication of perinuclear mitochondrial genotypes during morula and blastocyst formation.

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Pasion, S. G., G. W. Brown, L. M. Brown, and D. S. Ray. "Periodic expression of nuclear and mitochondrial DNA replication genes during the trypanosomatid cell cycle." Journal of Cell Science 107, no. 12 (December 1, 1994): 3515–20. http://dx.doi.org/10.1242/jcs.107.12.3515.

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In trypanosomatids, DNA replication in the nucleus and in the single mitochondrion (or kinetoplast) initiates nearly simultaneously, suggesting that the DNA synthesis (S) phases of the nucleus and the mitochondrion are coordinately regulated. To investigate the basis for the temporal link between nuclear and mitochondrial DNA synthesis phases the expression of the genes encoding DNA ligase I, the 51 and 28 kDa subunits of replication protein A, dihydrofolate reductase and the mitochondrial type II topoisomerase were analyzed during the cell cycle progression of synchronous cultures of Crithidia fasciculata. These DNA replication genes were all expressed periodically, with peak mRNA levels occurring just prior to or at the peak of DNA synthesis in the synchronized cultures. A plasmid clone (pdN-1) in which TOP2, the gene encoding the mitochondrial topoisomerase, was disrupted by the insertion of a NEO drug-resistance cassette was found to express both a truncated TOP2 mRNA and a truncated topoisomerase polypeptide. The truncated mRNA was also expressed periodically coordinate with the expression of the endogenous TOP2 mRNA indicating that cis elements necessary for periodic expression are contained within cloned sequences. The expression of both TOP2 and nuclear DNA replication genes at the G1/S boundary suggests that regulated expression of these genes may play a role in coordinating nuclear and mitochondrial S phases in trypanosomatids.

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Tang, Jintian, Leilei Zhang, Jinghan Su, Qingwen Ye, Yukang Li, Dinghang Liu, Haifeng Cui, Yafen Zhang, and Zihong Ye. "Insights into Fungal Mitochondrial Genomes and Inheritance Based on Current Findings from Yeast-like Fungi." Journal of Fungi 10, no. 7 (June 21, 2024): 441. http://dx.doi.org/10.3390/jof10070441.

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The primary functions of mitochondria are to produce energy and participate in the apoptosis of cells, with them being highly conserved among eukaryotes. However, the composition of mitochondrial genomes, mitochondrial DNA (mtDNA) replication, and mitochondrial inheritance varies significantly among animals, plants, and fungi. Especially in fungi, there exists a rich diversity of mitochondrial genomes, as well as various replication and inheritance mechanisms. Therefore, a comprehensive understanding of fungal mitochondria is crucial for unraveling the evolutionary history of mitochondria in eukaryotes. In this review, we have organized existing reports to systematically describe and summarize the composition of yeast-like fungal mitochondrial genomes from three perspectives: mitochondrial genome structure, encoded genes, and mobile elements. We have also provided a systematic overview of the mechanisms in mtDNA replication and mitochondrial inheritance during bisexual mating. Additionally, we have discussed and proposed open questions that require further investigation for clarification.

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Copeland, William C., and Matthew J. Longley. "DNA Polymerase Gamma in Mitochondrial DNA Replication and Repair." Scientific World JOURNAL 3 (2003): 34–44. http://dx.doi.org/10.1100/tsw.2003.09.

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Mutations in mitochondrial DNA (mtDNA) are associated with aging, and they can cause tissue degeneration and neuromuscular pathologies known as mitochondrial diseases. Because DNA polymerase γ (pol γ) is the enzyme responsible for replication and repair of mitochondrial DNA, the burden of faithful duplication of mitochondrial DNA, both in preventing spontaneous errors and in DNA repair synthesis, falls on pol γ. Investigating the biological functions of pol γ and its inhibitors aids our understanding of the sources of mtDNA mutations. In animal cells, pol γ is composed of two subunits, a larger catalytic subunit of 125–140 kDa and second subunit of 35–55 kDa. The catalytic subunit contains DNA polymerase activity, 3’-5’ exonuclease activity, and a 5’-dRP lyase activity. The accessory subunit is required for highly processive DNA synthesis and increases the affinity of pol gamma to the DNA.

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Unchwaniwala, Nuruddin, Nathan M. Sherer, and Daniel D. Loeb. "Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal." Journal of Virology 90, no. 19 (July 20, 2016): 8705–19. http://dx.doi.org/10.1128/jvi.01229-16.

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ABSTRACTTo understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-green fluorescent protein (Pol-GFP) fusions and found that a stretch spanning amino acids (aa) 141 to 160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting aa 141 to 160 in full-length Pol did not fully ablate Pol's mitochondrial localization, suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in full-length Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within aa 141 to 160, indicating a multifunctional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis.IMPORTANCEChronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a non-reverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis, and innate immunity. Pol may alter one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals.

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Jourdain, Alexis A., Erik Boehm, Kinsey Maundrell, and Jean-Claude Martinou. "Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression." Journal of Cell Biology 212, no. 6 (March 7, 2016): 611–14. http://dx.doi.org/10.1083/jcb.201507125.

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In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized “mitochondrial RNA granules,” mitochondrial subdomains with an emerging role in the regulation of gene expression.

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Clayton, D. A. "Transcription and replication of mitochondrial DNA." Human Reproduction 15, suppl 2 (July 1, 2000): 11–17. http://dx.doi.org/10.1093/humrep/15.suppl_2.11.

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Copeland, William C. "Inherited Mitochondrial Diseases of DNA Replication." Annual Review of Medicine 59, no. 1 (February 2008): 131–46. http://dx.doi.org/10.1146/annurev.med.59.053006.104646.

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Clayton, David. "Mitochondrial DNA Replication: What We Know." IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 55, no. 4-5 (January 1, 2003): 213–17. http://dx.doi.org/10.1080/1521654031000134824.

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Duxin, Julien P., Benjamin Dao, Peter Martinsson, Nina Rajala, Lionel Guittat, Judith L. Campbell, Johannes N. Spelbrink, and Sheila A. Stewart. "Human Dna2 Is a Nuclear and Mitochondrial DNA Maintenance Protein." Molecular and Cellular Biology 29, no. 15 (June 1, 2009): 4274–82. http://dx.doi.org/10.1128/mcb.01834-08.

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ABSTRACT Dna2 is a highly conserved helicase/nuclease that in yeast participates in Okazaki fragment processing, DNA repair, and telomere maintenance. Here, we investigated the biological function of human Dna2 (hDna2). Immunofluorescence and biochemical fractionation studies demonstrated that hDna2 was present in both the nucleus and the mitochondria. Analysis of mitochondrial hDna2 revealed that it colocalized with a subfraction of DNA-containing mitochondrial nucleoids in unperturbed cells. Upon the expression of disease-associated mutant forms of the mitochondrial Twinkle helicase which induce DNA replication pausing/stalling, hDna2 accumulated within nucleoids. RNA interference-mediated depletion of hDna2 led to a modest decrease in mitochondrial DNA replication intermediates and inefficient repair of damaged mitochondrial DNA. Importantly, hDna2 depletion also resulted in the appearance of aneuploid cells and the formation of internuclear chromatin bridges, indicating that nuclear hDna2 plays a role in genomic DNA stability. Together, our data indicate that hDna2 is similar to its yeast counterpart and is a new addition to the growing list of proteins that participate in both nuclear and mitochondrial DNA maintenance.

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Goffart, Steffi, Anu Hangas, and Jaakko L. O. Pohjoismäki. "Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance." International Journal of Molecular Sciences 20, no. 8 (April 25, 2019): 2041. http://dx.doi.org/10.3390/ijms20082041.

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Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2β and Top3α, enzymes that are shared between nucleus and mitochondria. Top3α mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2β, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.

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Xie, Bin, Hao Li, Qi Wang, Suqing Xie, Amal Rahmeh, Wei Dai, and Marietta Y. W. T. Lee. "Further Characterization of Human DNA Polymerase δ Interacting Protein 38." Journal of Biological Chemistry 280, no. 23 (April 4, 2005): 22375–84. http://dx.doi.org/10.1074/jbc.m414597200.

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Polymerase δ interacting protein 38 (PDIP38) was identified as a human DNA polymerase (pol) δ interacting protein through a direct interaction with p50, the small subunit of human pol δ. PDIP38 was also found to interact with proliferating cell nuclear antigen, which suggested that it might play a role in vivo in the processes of DNA replication and DNA repair in the nucleus. In order to characterize further this novel protein, we have examined its subcellular localization by the use of immunochemical and cellular fractionation techniques. These studies show that PDIP38 is a novel mitochondrial protein and is localized mainly to the mitochondria. PDIP38 was shown to possess a functional mitochondrial targeting sequence that is located within the first 35 N-terminal amino acid residues. The mature PDIP38 protein is about 50 amino acid residues smaller than the full-length precursor PDIP38 protein, consistent with it being processed by cleavage of the mitochondrial targeting sequence during entry into the mitochondria. His-tagged mature PDIP38 inhibited pol δ activity in vitro and interacted with human papillomavirus 16 E7 oncoprotein, suggesting that PDIP38 might play a role in the pol δ-mediated viral DNA replication. Although the localization of PDIP38 to the mitochondria suggests that it serves functions within the mitochondria, we cannot eliminate the possibility that it may be involved in pol δ-mediated DNA replication or DNA repair under certain conditions such as viral infection.

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Shaulsky, G., and W. F. Loomis. "Mitochondrial DNA replication but no nuclear DNA replication during development of Dictyostelium." Proceedings of the National Academy of Sciences 92, no. 12 (June 6, 1995): 5660–63. http://dx.doi.org/10.1073/pnas.92.12.5660.

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Maier, Dieter, Carol L. Farr, Burkhard Poeck, Anuradha Alahari, Marion Vogel, Susanne Fischer, Laurie S. Kaguni, and Stephan Schneuwly. "Mitochondrial Single-stranded DNA-binding Protein Is Required for Mitochondrial DNA Replication and Development in Drosophila melanogaster." Molecular Biology of the Cell 12, no. 4 (April 2001): 821–30. http://dx.doi.org/10.1091/mbc.12.4.821.

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The discovery that several inherited human diseases are caused by mtDNA depletion has led to an increased interest in the replication and maintenance of mtDNA. We have isolated a new mutant in thelopo (low power) gene fromDrosophila melanogaster affecting the mitochondrial single-stranded DNA-binding protein (mtSSB), which is one of the key components in mtDNA replication and maintenance.lopo 1 mutants die late in the third instar before completion of metamorphosis because of a failure in cell proliferation. Molecular, histochemical, and physiological experiments show a drastic decrease in mtDNA content that is coupled with the loss of respiration in these mutants. However, the number and morphology of mitochondria are not greatly affected. Immunocytochemical analysis shows that mtSSB is expressed in all tissues but is highly enriched in proliferating tissues and in the developing oocyte.lopo 1 is the first mtSSB mutant in higher eukaryotes, and its analysis demonstrates the essential function of this gene in development, providing an excellent model to study mitochondrial biogenesis in animals.

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Butler, Thomas J., Katrina N. Estep, Joshua A. Sommers, Robert W. Maul, Ann Zenobia Moore, Stefania Bandinelli, Francesco Cucca, et al. "Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro." Human Molecular Genetics 29, no. 8 (March 19, 2020): 1292–309. http://dx.doi.org/10.1093/hmg/ddaa043.

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Abstract As the powerhouses of the eukaryotic cell, mitochondria must maintain their genomes which encode proteins essential for energy production. Mitochondria are characterized by guanine-rich DNA sequences that spontaneously form unusual three-dimensional structures known as G-quadruplexes (G4). G4 structures can be problematic for the essential processes of DNA replication and transcription because they deter normal progression of the enzymatic-driven processes. In this study, we addressed the hypothesis that mitochondrial G4 is a source of mutagenesis leading to base-pair substitutions. Our computational analysis of 2757 individual genomes from two Italian population cohorts (SardiNIA and InCHIANTI) revealed a statistically significant enrichment of mitochondrial mutations within sequences corresponding to stable G4 DNA structures. Guided by the computational analysis results, we designed biochemical reconstitution experiments and demonstrated that DNA synthesis by two known mitochondrial DNA polymerases (Pol γ, PrimPol) in vitro was strongly blocked by representative stable G4 mitochondrial DNA structures, which could be overcome in a specific manner by the ATP-dependent G4-resolving helicase Pif1. However, error-prone DNA synthesis by PrimPol using the G4 template sequence persisted even in the presence of Pif1. Altogether, our results suggest that genetic variation is enriched in G-quadruplex regions that impede mitochondrial DNA replication.

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Hussain, Mansoor, Aftab Mohammed, Shabnam Saifi, Aamir Khan, Ekjot Kaur, Swati Priya, Himanshi Agarwal, and Sagar Sengupta. "MITOL-dependent ubiquitylation negatively regulates the entry of PolγA into mitochondria." PLOS Biology 19, no. 3 (March 3, 2021): e3001139. http://dx.doi.org/10.1371/journal.pbio.3001139.

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Mutations in mitochondrial replicative polymerase PolγA lead to progressive external ophthalmoplegia (PEO). While PolγA is the known central player in mitochondrial DNA (mtDNA) replication, it is unknown whether a regulatory process exists on the mitochondrial outer membrane which controlled its entry into the mitochondria. We now demonstrate that PolγA is ubiquitylated by mitochondrial E3 ligase, MITOL (or MARCH5, RNF153). Ubiquitylation in wild-type (WT) PolγA occurs at Lysine 1060 residue via K6 linkage. Ubiquitylation of PolγA negatively regulates its binding to Tom20 and thereby its mitochondrial entry. While screening different PEO patients for mitochondrial entry, we found that a subset of the PolγA mutants is hyperubiquitylated by MITOL and interact less with Tom20. These PolγA variants cannot enter into mitochondria, instead becomes enriched in the insoluble fraction and undergo enhanced degradation. Hence, mtDNA replication, as observed via BrdU incorporation into the mtDNA, was compromised in these PEO mutants. However, by manipulating their ubiquitylation status by 2 independent techniques, these PEO mutants were reactivated, which allowed the incorporation of BrdU into mtDNA. Thus, regulated entry of non-ubiquitylated PolγA may have beneficial consequences for certain PEO patients.

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RIEDINGER, Hans-Jörg, Frank EGER, Klaus TRUMMLER, and Hans PROBST. "Replication of simian virus 40 (SV40) DNA in virus-infected CV1 cells selectively permeabilized for small molecules by Staphylococcus aureus α-toxin: involvement of mitochondria in the fast O2-dependent regulation of SV40 DNA replication." Biochemical Journal 386, no. 3 (March 8, 2005): 557–66. http://dx.doi.org/10.1042/bj20040492.

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SV40 (simian virus 40)-infected CV1 cells were permeabilized with Staphylococcus aureus α-toxin for small molecules (<2 kDa) in a medium that supports DNA replication. Incorporation of [α-32P]dATP was shown to proceed at an essentially constant rate for at least 1 h. 32P-labelled DNA replication intermediates and products were analysed by alkaline sucrose density centrifugation. The results suggested that SV40 DNA replication in α-toxin-permeabilized CV1 cells occurred essentially as in vivo. After bromodeoxyuridine 5′-triphosphate-labelling and isopycnic banding, significant amounts of DNA density-labelled in both strands were detected from 110 min of permeabilization onwards, indicating repeated rounds of viral DNA replication in the permeabilized cells. Incubation of permeabilized SV40-infected cells under hypoxic culture conditions caused inhibition of SV40 DNA replication. As seen in unpermeabilized cells, SV40 DNA replication was inhibited at the stage of initiation. The inhibition of DNA replication induced by hypoxia was mimicked by AA (antimycin A), an inhibitor of mitochondrial respiration, and also by the replacement of glutamate, a substrate of mitochondrial respiration, by Hepes in the permeabilization medium. Inhibition of DNA replication was not mediated by intracellular ATP depletion. AA also inhibited SV40 DNA replication in unpermeabilized, normoxically incubated cells. Moreover, as in hypoxically incubated cells, the addition of glucose to SV40-infected cells incubated for several hours with AA induced a burst of new initiations followed by a nearly synchronous round of viral DNA replication. Taken together, these results indicate that mitochondria are involved in the oxygen-dependent regulation of SV40 DNA replication.

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Kennedy, J. M., S. R. Lobacz, and S. W. Kelley. "Mitochondrial DNA replication and transcription are dissociated during embryonic cardiac hypertrophy." American Journal of Physiology-Cell Physiology 261, no. 6 (December 1, 1991): C1091—C1098. http://dx.doi.org/10.1152/ajpcell.1991.261.6.c1091.

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Cardiac hypertrophy was produced in embryonic chicks by decreasing the incubation temperature from 38 degrees C to 32 degrees C on day 11. Increases in ventricular protein, RNA, and DNA support the cardiac enlargement. Cytochrome-c oxidase activity and citrate synthase activity were depressed in hypothermic ventricles by 63% and 56%, respectively. No significant differences were seen in enzyme activities in pectoralis muscles. The involvement of mitochondrial gene replication and transcription was evaluated using a cDNA clone for the mitochondrially encoded subunit III of cytochrome-c oxidase (CO III). Quantitative slot-blot analysis demonstrated that the relative CO III mRNA concentration was reduced in hypothermic ventricles. In contrast, the relative mitochondrial DNA concentration was increased in hypothermic ventricles. Taken together, these data indicate that a hypothermia-induced decrease in cytochrome-c oxidase activity is associated with a decrease in CO III mRNA, which is not coupled to a decrease in the mitochondrial DNA copy number. This dissociation of mitochondrial gene replication and transcription may provide a useful model for examining the regulation of mitochondrial biogenesis.

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Amir, Muhammad, Sabeera Afzal, and Alia Ishaq. "PrimPol (Primase/Polymerase), replicating enzyme – A mini review." Pak-Euro Journal of Medical and Life Sciences 2, no. 4 (April 3, 2020): 89–92. http://dx.doi.org/10.31580/pjmls.v2i4.956.

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Polymerases were revealed first in 1970s. Most important to the modest perception the enzyme responsible for nuclear DNA replication that was pol , for DNA repair pol and for mitochondrial DNA replication pol DNA construction and renovation done by DNA polymerases, so directing both the constancy and discrepancy of genetic information. Replication of genome initiate with DNA template-dependent fusion of small primers of RNA. This preliminary phase in replication of DNA demarcated as de novo primer synthesis which is catalyzed by specified polymerases known as primases. Sixteen diverse DNA-synthesizing enzymes about human perspective are devoted to replication, reparation, mutilation lenience, and inconsistency of nuclear DNA. But in dissimilarity, merely one DNA polymerase has been called in mitochondria. It has been suggest that PrimPol is extremely acting the roles by re-priming DNA replication in mitochondria to permit an effective and appropriate way replication to be accomplished. Investigations from a numeral of test site have significantly amplified our appreciative of the role, recruitment and regulation of the enzyme during DNA replication. Though, we are simply just start to increase in value the versatile roles that play PrimPol in eukaryote.

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Mendoza, Hector, Michael H. Perlin, and Jan Schirawski. "Mitochondrial Inheritance in Phytopathogenic Fungi—Everything Is Known, or Is It?" International Journal of Molecular Sciences 21, no. 11 (May 29, 2020): 3883. http://dx.doi.org/10.3390/ijms21113883.

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Mitochondria are important organelles in eukaryotes that provide energy for cellular processes. Their function is highly conserved and depends on the expression of nuclear encoded genes and genes encoded in the organellar genome. Mitochondrial DNA replication is independent of the replication control of nuclear DNA and as such, mitochondria may behave as selfish elements, so they need to be controlled, maintained and reliably inherited to progeny. Phytopathogenic fungi meet with special environmental challenges within the plant host that might depend on and influence mitochondrial functions and services. We find that this topic is basically unexplored in the literature, so this review largely depends on work published in other systems. In trying to answer elemental questions on mitochondrial functioning, we aim to introduce the aspect of mitochondrial functions and services to the study of plant-microbe-interactions and stimulate phytopathologists to consider research on this important organelle in their future projects.

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RADOMSKI, JAN P., and S. MOSS DE OLIVEIRA. "SIMULATING THE MITOCHONDRIAL DNA BOTTLENECK." International Journal of Modern Physics C 11, no. 07 (October 2000): 1297–304. http://dx.doi.org/10.1142/s0129183100001140.

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A probabilistic model is proposed with dynamics which naturally leads to a bottleneck in the number of mitochondria transmitted from one host-cell generation to the other. We take into account deleterious mutations during the replication of mitochondria within a cell of a germ-line and introduce selection inside the cell reproduction mechanism. The bottleneck size strongly depends on the selection mechanism and on the maximum number of mitochondria per cell. We obtain that the smaller the maximum allowed number of mitochondria per cell during replication, the tighter the bottleneck. Such a result is in agreement with the fact that species producing small litters provide developing oocytes with a smaller number of mitochondria. This amplifies the differences among oocytes leading to competition and removal of inferior cells.

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Drew, Mark E., and Paul T. Englund. "Intramitochondrial Location and Dynamics of Crithidia fasciculata Kinetoplast Minicircle Replication Intermediates." Journal of Cell Biology 153, no. 4 (May 7, 2001): 735–44. http://dx.doi.org/10.1083/jcb.153.4.735.

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Kinetoplast DNA, the mitochondrial DNA of Crithidia fasciculata, is organized into a network containing 5,000 topologically interlocked minicircles. This network, situated within the mitochondrial matrix, is condensed into a disk-shaped structure located near the basal body of the flagellum. Fluorescence in situ hybridization revealed that before their replication, minicircles are released vectorially from the network face nearest the flagellum. Replication initiates in the zone between the flagellar face of the disk and the mitochondrial membrane (we term this region the kinetoflagellar zone [KFZ]). The replicating minicircles then move to two antipodal sites that flank the disk-shaped network. In later stages of replication, the number of free minicircles increases, accumulating transiently in the KFZ. The final replication events, including primer removal, repair of many of the gaps, and reattachment of the progeny minicircles to the network periphery, are thought to take place within the antipodal sites.

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Engman, D. M., L. V. Kirchhoff, and J. E. Donelson. "Molecular cloning of mtp70, a mitochondrial member of the hsp70 family." Molecular and Cellular Biology 9, no. 11 (November 1989): 5163–68. http://dx.doi.org/10.1128/mcb.9.11.5163-5168.1989.

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We have isolated a gene from the protozoan parasite Trypanosoma cruzi that encodes a previously unidentified member of the 70-kilodalton heat shock protein (hsp70) family. Among all the eucaryotic hsp70 proteins described to date, this trypanosome protein, mtp70, is uniquely related in sequence and structure to the hsp70 of Escherichia coli, DnaK, which functions in the initiation of DNA replication. This relationship to DnaK is especially relevant in view of the intracellular location of the protein. Within the trypanosome, mtp70 is located in the mitochondrion, where it associates with kinetoplast DNA (kDNA), the unusual mitochondrial DNA that distinguishes this order of protozoa. Moreover, mtp70 is located in the specific region of the kinetoplast in which kDNA replication occurs. In view of the known functions of DnaK, the localization of mtp70 to the site of kDNA replication suggests that mtp70 may participate in eucaryotic mitochondrial DNA replication in a manner analogous to that of DnaK in E. coli.

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Engman, D. M., L. V. Kirchhoff, and J. E. Donelson. "Molecular cloning of mtp70, a mitochondrial member of the hsp70 family." Molecular and Cellular Biology 9, no. 11 (November 1989): 5163–68. http://dx.doi.org/10.1128/mcb.9.11.5163.

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We have isolated a gene from the protozoan parasite Trypanosoma cruzi that encodes a previously unidentified member of the 70-kilodalton heat shock protein (hsp70) family. Among all the eucaryotic hsp70 proteins described to date, this trypanosome protein, mtp70, is uniquely related in sequence and structure to the hsp70 of Escherichia coli, DnaK, which functions in the initiation of DNA replication. This relationship to DnaK is especially relevant in view of the intracellular location of the protein. Within the trypanosome, mtp70 is located in the mitochondrion, where it associates with kinetoplast DNA (kDNA), the unusual mitochondrial DNA that distinguishes this order of protozoa. Moreover, mtp70 is located in the specific region of the kinetoplast in which kDNA replication occurs. In view of the known functions of DnaK, the localization of mtp70 to the site of kDNA replication suggests that mtp70 may participate in eucaryotic mitochondrial DNA replication in a manner analogous to that of DnaK in E. coli.

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Graziewicz, Maria A., Matthew J. Longley, and William C. Copeland. "DNA Polymerase γ in Mitochondrial DNA Replication and Repair." Chemical Reviews 106, no. 2 (February 2006): 383–405. http://dx.doi.org/10.1021/cr040463d.

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Chapman, James, Yi Shiau Ng, and Thomas J. Nicholls. "The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes." Life 10, no. 9 (August 26, 2020): 164. http://dx.doi.org/10.3390/life10090164.

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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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Backert, S., P. Dörfel, R. Lurz, and T. Börner. "Rolling-circle replication of mitochondrial DNA in the higher plant Chenopodium album (L.)." Molecular and Cellular Biology 16, no. 11 (November 1996): 6285–94. http://dx.doi.org/10.1128/mcb.16.11.6285.

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The mitochondrial genomes of higher plants are larger and more complex than those of all other groups of organisms. We have studied the in vivo replication of chromosomal and plasmid mitochondrial DNAs prepared from a suspension culture and whole plants of the dicotyledonous higher plant Chenopodium album (L.). Electron microscopic studies revealed sigma-shaped, linear, and open circular molecules (subgenomic circles) of variable size as well as a minicircular plasmid of 1.3 kb (mp1). The distribution of single-stranded mitochondrial DNA in the sigma structures and the detection of entirely single-stranded molecules indicate a rolling-circle type of replication of plasmid mp1 and subgenomic circles. About half of the sigma-like molecules had tails exceeding the lengths of the corresponding circle, suggesting the formation of concatemers. Two replication origins (nicking sites) could be identified on mpl by electron microscopy and by a new approach based on the mapping of restriction fragments representing the identical 5' ends of the tails of sigma-like molecules. These data provide, for the first time, evidence for a rolling-circle mode of replication in the mitochondria of higher plants.

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Journal articles on the topic 'Mitochondrial DNA replication'

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