scholarly journals Mitochondrial DNA Integrity: Role in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 100 ◽  
Author(s):  
Priyanka Sharma ◽  
Harini Sampath
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Genome Stability ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Age Related ◽  
Genome Damage ◽  
Health And Disease ◽  
Mitochondrial Genome Stability

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

scholarly journals Reduced Shmt2 expression impairs mitochondrial folate accumulation and respiration, and leads to uracil accumulation in mouse mitochondrial DNA

2021 ◽  
Author(s):  
Joanna L Fiddler ◽  
Yuwen Xiu ◽  
Jamie E Blum ◽  
Simon G Lamarre ◽  
Whitney N Phinney ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Folic Acid ◽  
Mitochondrial Function ◽  
Genome Stability ◽  
Control Diet ◽  
Folate Deficiency ◽  
Dna Integrity ◽  
Dietary Folate ◽  
Mouse Tissues ◽  
Defined Culture

Background. Adequate cellular thymidylate (dTMP) pools are essential for preservation of nuclear and mitochondrial genome stability. Previous studies have indicated that disruption in dTMP synthesis in the nucleus leads to increased uracil misincorporation into DNA affecting genome stability. To date, the effects of impaired mitochondrial dTMP synthesis in non-transformed tissues have been understudied. Objective. This study aimed to determine the effects of decreased serine hydroxymethyltransferase 2 (Shmt2) expression and dietary folate deficiency on mitochondrial DNA integrity and mitochondrial function in mouse tissues. Methods. Liver mitochondrial DNA (mtDNA) content, and uracil content in liver mtDNA was measured in Shmt2+/- and Shmt2+/+ mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a modified diet lacking folic acid (0 mg/kg folic acid, FD) for 7 wks. Shmt2+/- and Shmt2+/+ mouse embryonic fibroblasts (MEF cells) were cultured in defined culture medium containing either 0 or 25 nM folate to assess proliferative capacity and mitochondrial function. Results. Shmt2+/- mice exhibited 48-67% reduction in SHMT2 protein levels in tissues. Interestingly, Shmt2+/- mice consuming the folate-sufficient C diet exhibited a 25% reduction in total folate in liver mitochondria. There was also a >20-fold increase in uracil in liver mtDNA in Shmt2+/- mice consuming the C diet, and dietary folate deficiency also increased uracil content in mouse liver mtDNA from both Shmt2+/+ and Shmt2+/- mice. Furthermore, decreased Shmt2 expression in MEF cells reduced cell proliferation, mitochondrial membrane potential, and oxygen consumption rate. Conclusions. This study demonstrates that Shmt2 heterozygosity and dietary folate deficiency impair mitochondrial dTMP synthesis, as evidenced by the increased uracil in mtDNA. In addition, Shmt2 heterozygosity impairs mitochondrial function in MEF cells. These findings suggest that elevated uracil in mtDNA may impair mitochondrial function.

scholarly journals Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1205 ◽  
Author(s):  
Riccardo Miggiano ◽  
Castrese Morrone ◽  
Franca Rossi ◽  
Menico Rizzi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Genome Stability ◽  
Current Knowledge ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Dna Metabolism ◽  
Nucleotide Synthesis ◽  
Antitubercular Drugs ◽  
Molecular Events

Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity.

scholarly journals Acid Phosphatases of Budding Yeast as a Model of Choice for Transcription Regulation Research

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Elena V. Sambuk ◽  
Anastasia Yu. Fizikova ◽  
Vladimir A. Savinov ◽  
Marina V. Padkina
Keyword(s):  
Mitochondrial Genome ◽  
Genome Stability ◽  
Budding Yeast ◽  
Transcriptional Regulator ◽  
Special Focus ◽  
Acid Phosphatases ◽  
Cyclin Dependent Kinase ◽  
Biochemical Characteristics ◽  
Eukaryotic Genes ◽  
Mitochondrial Genome Stability

Acid phosphatases of budding yeast have been studied for more than forty years. This paper covers biochemical characteristics of acid phosphatases and different aspects in expression regulation of eukaryotic genes, which were researched using acid phosphatases model. A special focus is devoted to cyclin-dependent kinase Pho85p, a negative transcriptional regulator, and its role in maintaining mitochondrial genome stability and to pleiotropic effects of pho85 mutations.

The influence of mitochondrial dynamics on mitochondrial genome stability

2017 ◽  
Vol 64 (1) ◽  
pp. 199-214 ◽  
Author(s):  
Christopher T. Prevost ◽  
Nicole Peris ◽  
Christina Seger ◽  
Deanna R. Pedeville ◽  
Kathryn Wershing ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Genome Stability ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Genome Stability

scholarly journals MMS19 localizes to mitochondria and protects the mitochondrial genome from oxidative damage

2018 ◽  
Vol 96 (1) ◽  
pp. 44-49 ◽  
Author(s):  
Rui Wu ◽  
Qunsong Tan ◽  
Kaifeng Niu ◽  
Yuqi Zhu ◽  
Di Wei ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Oxidative Damage ◽  
Genome Stability ◽  
Excision Repair ◽  
Mass Spectrometry Analysis ◽  
Mtdna Copy Number ◽  
Repair Capacity ◽  
Spectrometry Analysis ◽  
Mitochondrial Genome Stability ◽  
Mtdna Repair

MMS19 localizes to the cytoplasmic and nuclear compartments involved in transcription and nucleotide excision repair (NER). However, whether MMS19 localizes to mitochondria, where it plays a role in maintaining mitochondrial genome stability, remains unknown. In this study, we provide the first evidence that MMS19 is localized in the inner membrane of mitochondria and participates in mtDNA oxidative damage repair. MMS19 knockdown led to mitochondrial dysfunctions including decreased mtDNA copy number, diminished mtDNA repair capacity, and elevated levels of mtDNA common deletion after oxidative stress. Immunoprecipitation – mass spectrometry analysis identified that MMS19 interacts with ANT2, a protein associated with mitochondrial ATP metabolism. ANT2 knockdown also resulted in a decreased mtDNA repair capacity after oxidative damage. Our findings suggest that MMS19 plays an essential role in maintaining mitochondrial genome stability.

scholarly journals The Importance of Mitochondrial DNA in Aging and Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Claus Desler ◽  
Maiken Lise Marcker ◽  
Keshav K. Singh ◽  
Lene Juel Rasmussen
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Mitochondrial Dysfunction ◽  
Premature Aging ◽  
Tumor Initiation ◽  
Pathological Conditions ◽  
Contemporary View ◽  
Age Related ◽  
Mitochondrial Ros ◽  
Altered Regulation

Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides.

scholarly journals Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair

2009 ◽  
Vol 18 (20) ◽  
pp. 3832-3850 ◽  
Author(s):  
Oliver Rothfuss ◽  
Heike Fischer ◽  
Takafumi Hasegawa ◽  
Martina Maisel ◽  
Petra Leitner ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Genome Integrity ◽  
Mitochondrial Dna Repair
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