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Exercise Training, Mitochondrial Adaptations, and Aging
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Nashwa Cheema, Matthew Triolo, David A. Hood
Each mitochondrion possesses numerous copies of its own circular DNA (mtDNA), which is approximately 16.5 kb in size and contains 37 genes (6). The nuclear-encoded mitochondrial RNA polymerase (POLRMT), mitochondrial transcription factors B1 and B2 (TFB1/2M), and Tfam mediate mtDNA transcription and replication (7, 46). Nuclear transcription of Tfam, TFB1M, and TFB2M are activated by NRF-1 and NRF-2 and co-activated by PGC-1 α. This represents an integral connection between the two genomes in the process of organelle synthesis (55, 176).
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Although contribution of the replicative machinery to the stability of mitochondrial DNA seems straightforward it is not so in case of transcription. There are several features that may explain the involvement of transcription machinery in mtDNA maintenance. First, mtDNAs are not lonely molecules floating in the mitochondrial matrix. In fact mitochondrial DNA molecules are organized in so-called nucleoids in which the protein DNA complexes remain attached to the mitochondrial inner membrane. The proteins forming nucleoids are responsible for mtDNA replication, repair and transcription. This means that transcription and replication machinery are acting in the same place. They also, to some extent, act at the same time as RNA polymerase (POLRMT) is involved in priming replication.
Oregonin from Alnus incana bark affects DNA methyltransferases expression and mitochondrial DNA copies in mouse embryonic fibroblasts
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jelena Krasilnikova, Liga Lauberte, Elena Stoyanova, Desislava Abadjieva, Mihail Chervenkov, Mattia Mori, Elisa De Paolis, Vanya Mladenova, Galina Telysheva, Bruno Botta, Elena Kistanova
Changes in mtDNA copy number have been reported in a broad range of human diseases44, such as diabetes and its complications, obesity, cancer, HIV complications and ageing. Our interest in the investigation of this parameter was triggered by the evidence of important role of mitochondria in the DNA methylation process and remarkable antioxidant properties of oregonin. Results described in this work clearly show the ability of oregonin to increase the mtDNA content in the investigated cells although this effect is quantitatively dependent on the cell type, as NIH/3T3 cells showed more genomic stability than MEFs. The drastic increase of mtDNA content in MEFs treated with 100 μM was accompanied by a decrease of cell viability at 24 h. Most likely, there is an adaptive response to increase oxidative stress by an enhancement of mitochondrial biogenesis due to toxic dose of oregonin44. On the other hand, these changes also correspond to the increase of Dnmts expression in MEFs. Our study highlighted for the first time the close relationship between changes in mtDNA content and expression of Dnmts mRNAs, which could be explained by considering that DNMTs enzymatic function is depended on the methyl donor SAM, whose proper production is guaranteed also by mitochondria18. The dependence of the DNA methylation process on the mitochondria content is confirmed by Smiraglia et al.19, who analyse the methylation status of several genes in response to the depletion and repletion of mtDNA. However, the mechanism provoked by oregonin to increase the mtDNA replication is still unclear. The replication of the mitochondrial genome is regulated via the actions of a combination of gene expression coding in mtDNA and nuclear DNA such as d-loop region of mtDNA, TFAM, RNA polymerase (POLRMT), DNA polymerase POLG, transcription factors 1 and 2 (TFB1Mand TFB2M), nuclear respiratory factors 1 and 2 (NRF-1, NRF-2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α)45–48. Oregonin could affect these genes via genetic or epigenetic pathways due to its ability to change the expression of Dnmts. Additionally, the anti-oxidative properties of oregonin result in an alteration of the mRNA expression of several antioxidant-related genes and oxidative stress responsive genes10, which could explain the increase in mtDNA copy number through the communication between nuclear and mitochondrial genes.