Mitochondrial DNA damage as driver of cellular outcomes

2021 ◽  
Author(s):  
Cristina A Nadalutti ◽  
Sylvette Ayala-Peña ◽  
Janine H. Santos
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Blood Cells ◽  
Energy Production ◽  
Nuclear Dna ◽  
Genetic Material ◽  
Genetic Alterations ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Cellular Dysfunction

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, which is 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 every cell contains hundreds to thousands of mitochondria, it follows that the shear number of organelles allow 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. While 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.

scholarly journals p53 is required for nuclear but not mitochondrial DNA damage-induced degeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthew J. Geden ◽  
Selena E. Romero ◽  
Mohanish Deshmukh
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Neuronal Cell ◽  
Axon Degeneration ◽  
Whole Cell ◽  
Axon Pruning ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Neuronal Cell Bodies

AbstractWhile the consequences of nuclear DNA damage have been well studied, the exact consequences of acute and selective mitochondrial DNA (mtDNA) damage are less understood. DNA damaging chemotherapeutic drugs are known to activate p53-dependent apoptosis in response to sustained nuclear DNA damage. While it is recognized that whole-cell exposure to these drugs also damages mtDNA, the specific contribution of mtDNA damage to cellular degeneration is less clear. To examine this, we induced selective mtDNA damage in neuronal axons using microfluidic chambers that allow for the spatial and fluidic isolation of neuronal cell bodies (containing nucleus and mitochondria) from the axons (containing mitochondria). Exposure of the DNA damaging drug cisplatin selectively to only the axons induced mtDNA damage in axonal mitochondria, without nuclear damage. We found that this resulted in the selective degeneration of only the targeted axons that were exposed to DNA damage, where ROS was induced but mitochondria were not permeabilized. mtDNA damage-induced axon degeneration was not mediated by any of the three known axon degeneration pathways: apoptosis, axon pruning, and Wallerian degeneration, as Bax-deficiency, or Casp3-deficiency, or Sarm1-deficiency failed to protect the degenerating axons. Strikingly, p53, which is essential for degeneration after nuclear DNA damage, was also not required for degeneration induced with mtDNA damage. This was most evident when the p53-deficient neurons were globally exposed to cisplatin. While the cell bodies of p53-deficient neurons were protected from degeneration in this context, the axons farthest from the cell bodies still underwent degeneration. These results highlight how whole cell exposure to DNA damage activates two pathways of degeneration; a faster, p53-dependent apoptotic degeneration that is triggered in the cell bodies with nuclear DNA damage, and a slower, p53-independent degeneration that is induced with mtDNA damage.

scholarly journals Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

2021 ◽  
Author(s):  
George B. Stefano ◽  
Richard M. Kream
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Neurological Disorders ◽  
Nuclear Dna ◽  
Mitochondrial Dynamics ◽  
Cell Types ◽  
Tissue Specific ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

Abstract 11852: Role of Lox-1 in Mitochondrial Dna Damage and NLRP3 Inflammasome Activation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zufeng Ding ◽  
Sadip Pant ◽  
Abhishek Deshmukh ◽  
Jawahar L Mehta
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Nlrp3 Inflammasome ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Objective: This study tested the hypothesis that mitochondrial DNA damage could trigger NLRP3 inflammasome activation during inflammation, and LOX-1 may play a critical role in this process. Methods and Results: We performed studies in cultured human THP1 macrophages exposed to ox-LDL or LPS,which are often used as inflammation stimuli in vitro . We examined and confirmed the increase in LOX-1 expression when cells were treated with ox-LDL or LPS. Parallel groups of cells were treated with LOX-1 Ab to bind LOX-1. In accordance with our previous studies in endothelial cells and smooth muscle cells, LOX-1 Ab markedly reduced ox-LDL- as well as LPS-stimulated LOX-1 expression. To assess mitochondrial ROS generation, MitoSOX™ Red mitochondrial superoxide indicator was used. Both fluorescence staining and flow cytometry analysis showed that LPS induced (more than ox-LDL) mitochondrial ROS generation. Pretreatment with LOX-1 Ab significantly attenuated mitochondrial ROS generation in response to ox-LDL or LPS. Then we observed mtDNA damage in THP1 cells exposed to ox-LDL or LPS. Importantly, pretreatment with LOX-1 Ab protected mtDNA from damage in response to both stimuli. This was also confirmed by q-PCR (mtDNA/nDNA ratio) analysis. Further, ox-LDL or LPS induced the expression of phos-NF-kB p65, caspase-1 p10 and p20, and cleaved proteins IL-1β and IL-18. Of note, NLRP3 inflammasome was activated in response to ox-LDL or LPS in a similar manner. Pretreatment of cells with LOX-1 Ab treatment blocked or significantly attenuated these inflammatory responses. Conclusions: These observations based on in vitro observations indicate that LOX-1 via ROS generation plays a key role in mtDNA damage which then leads to NLRP3 inflammasome activation during inflammation.

scholarly journals Genetic variability of farmed fur animals of the Canidae family assessed by nuclear and mitochondrial DNA analysis

2016 ◽  
Vol 72 (8) ◽  
pp. 505-510 ◽  
Author(s):  
Sylwia Nisztuk-Pacek
Keyword(s):  
Mitochondrial Dna ◽  
Dna Analysis ◽  
Nuclear Dna ◽  
Mitochondrial Gene ◽  
Genetic Material ◽  
Cox1 Gene ◽  
Phylogenetic Distance ◽  
Raccoon Dog ◽  
Study Results ◽  
Fur Animals

The aim of the study was to assess the biodiversity of farmed fur animals from the Canidae family (common fox, polar fox, and raccoon dog) using nuclear and mitochondrial markers. The study involved 434 animals. The biological material included whole peripheral blood or skin tissue. The isolated genetic material was subjected to qualitative and quantitative analyses. Mitochondrial DNA (mtDNA) gene fragments (COX1, COX2, CYTB) and nuclear DNA (nDNA) gene fragments (MSTN1, MSTN2, MSTN3, IGF1, GHR) were amplified with the PCR (polymerase chain reaction) technique. The amplicons obtained were sequenced or subjected to PCR-RFLP (restriction fragment length polymorphism) reaction, and bioinformatics analyses were performed. The interspecific analysis of the nDNA sequences revealed a total of 25 polymorphisms. On the other hand, the interspecific analysis of the mtDNA gene fragments identified 277 polymorphisms. The COX1 gene fragment exhibited the greatest variability. It was shown that the frequency of polymorphisms within the mitochondrial genome was almost 20-fold higher than that in the nuclear genome of the raccoon dog. It was found that the genetic distances revealed by the analysis of the mitochondrial gene fragments were similar to the results obtained by the nDNA analysis. The genetic distance between the raccoon and common fox was the greatest. The smallest phylogenetic distance was revealed between the two fox species. The study results indicate mitochondrial and nuclear genes may be alternatively used for determining the phylogenetic relationships between fur animals from the Canidae family.

scholarly journals Mitochondrial DNA, a Powerful Tool to Decipher Ancient Human Civilization from Domestication to Music, and to Uncover Historical Murder Cases

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 433 ◽  
Author(s):  
Maxime Merheb ◽  
Rachel Matar ◽  
Rawad Hodeify ◽  
Shoib Sarwar Siddiqui ◽  
Cijo George Vazhappilly ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Analysis ◽  
Nuclear Dna ◽  
Genetic Material ◽  
Modern Science ◽  
Criminal Cases ◽  
Trade Routes ◽  
Ancient Trade ◽  
Degraded Samples ◽  
Mtdna Sequence

Mitochondria are unique organelles carrying their own genetic material, independent from that in the nucleus. This review will discuss the nature of mitochondrial DNA (mtDNA) and its levels in the cell, which are the key elements to consider when trying to achieve molecular identification in ancient and degraded samples. mtDNA sequence analysis has been appropriately validated and is a consistent molecular target for the examination of biological evidence encountered in forensic cases—and profiling, in certain conditions—especially for burnt bodies and degraded samples of all types. Exceptional cases and samples will be discussed in this review, such as mtDNA from leather in Beethoven’s grand piano, mtDNA in mummies, and solving famous historical criminal cases. In addition, this review will be discussing the use of ancient mtDNA to understand past human diet, to trace historical civilizations and ancient trade routes, and to uncover geographical domestication origins and lineage relationships. In each topic, we will present the power of mtDNA and how, in many cases, no nuclear DNA was left, leaving mitochondrial DNA analysis as a powerful alternative. Exploring this powerful tool further will be extremely useful to modern science and researchers, due to its capabilities in providing us with previously unattainable knowledge.

Abstract 219: Diabetes-induced Mitochondrial Dna Damage and Cardiac Dysfunction are Aggravated Due to Low Aldehyde Dehydrogenase 2 (aldh2) Activity in Aldh 2*2 (e487k) Knock-in Mutant Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Suresh S Palaniyandi ◽  
Gudong Pan ◽  
Mandar Deshpande ◽  
Vishal R Mali ◽  
Jiang Xu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Aldehyde Dehydrogenase ◽  
Mitochondrial Respiration ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Cardiac Damage ◽  
Respiratory Dysfunction ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
C57bl Mice

A prevalent mutation (E487K) in aldehyde dehydrogenase (ALDH) 2, a cardiac mitochondrial enzyme, in East Asians (ALDH2*2) reduces ALDH2 activity and thereby increases aldehyde toxicity. Decreased ALDH2 activity is associated with cardiovascular diseases in humans and animal models. In this study, we hypothesized that reduction in ALDH2 activity in ALDH2*2 mice is sufficient to increase 4-hydroxy-2-nonenal (4HNE) levels and impair mitochondrial respiration and consequently induce cardiac damage in diabetes mellitus (DM). To test the hypothesis, streptozotocin (150 mg/kg i.p.) injected type-1 diabetic ALDH2*2 and C57BL mice as well as corresponding non-diabetic mice were employed. Four experimental groups were C57BL Control, C57BL DM, ALDH2*2 Control, and ALDH2*2 DM. N=6. Data were presented below in the same order. The mice were sacrificed after 3 weeks of DM. Myocardial ALDH2 activity and levels were reduced and 4HNE protein adducts were increased in ALDH2*2 DM mice relative to C57BL DM mice. Decrease in mitochondrial respiration was higher in ALDH2*2 DM mice compared to C57BL DM. Increase in cardiac hypertrophy (207 ± 8, 355 ± 4, 289 ± 22, 370 ± 20 in μm2; $$P<0.01 ALDH2*2 DM vs C57 DM) and fibrosis (4 ± 0.4, 8 ± 0.5, 6 ± 0.7, 9 ± 2.3 in % area of fibrosis; $$P<0.01 ALDH2*2 DM vs C57 DM) were higher in ALDH2*2 DM mice compared to C57BL DM. But the contractile function (56 ± 0.7, 54 ± 1.6, 43 ± 2.7, 48 ± 1.8 in %FS; $p <0.05 ALDH2*2 DM vs C57 DM) was lower only in ALDH2*2 DM, not WT DM. At the molecular level, increased mitochondrial DNA (mtDNA) damage and resultant decrease in MtDNA-encoded respiratory complex proteins were potentiated in diabetic ALDH2*2 mice compared to C57BL DM mice. Based on our data, we conclude that reduced ALDH2 activity in ALDH2*2 mice aggravated diabetes-induced cardiac mitochondrial respiratory dysfunction, ventricular remodeling and dysfunction.

Comparison of the levels of the 21S mitochondrial rRNA in derepressed and glucose-repressed Saccharomyces cerevisiae

1983 ◽  
Vol 3 (11) ◽  
pp. 1949-1957
Author(s):  
R Kelly ◽  
S L Phillips
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Nuclear Dna ◽  
Glucose Repression ◽  
Cellular Level ◽  
Rrna Gene ◽  
Mitochondrial Rna ◽  
Mitochondrial Rrna ◽  
Cdna Preparation

A cDNA preparation, synthesized by using Saccharomyces cerevisiae mitochondrial RNA as template and oligodeoxythymidylic acid as primer, was found to specifically hybridize to the mitochondrial 21S rRNA by the following criteria: (i) it hybridizes only to the 21S RNA species in mitochondrial RNA and not to RNA from a [rho0] mutant, and (ii) it hybridizes to fragments in restriction digests of mitochondrial DNA that contain the 21S rRNA gene but not to nuclear DNA. This cDNA was used as a probe to demonstrate that a 2.6-fold decrease in the cellular level of the mitochondrial large rRNA is associated with glucose repression of mitochondrial function in S. cerevisiae. A corresponding decrease in the level of mitochondrial DNA was not observed.

scholarly journals Viscum albumL. Extracts Protects HeLa Cells against Nuclear and Mitochondrial DNA Damage

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Evren Önay-Uçar ◽  
Özlem Erol ◽  
Başak Kandemir ◽  
Elif Mertoğlu ◽  
Ali Karagöz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Hela Cells ◽  
Oxidative Dna Damage ◽  
Nuclear Dna ◽  
Viscum Album ◽  
Mitochondrial Dna Damage ◽  
Methanolic Extracts ◽  
Host Trees ◽  
Lime Tree

Viscum albumL. is a semiparasitic plant grown on trees and widely used for the treatment of many diseases in traditional and complementary therapy. It is well known that some activities ofViscum albumextracts are varied depending on the host trees, such as antioxidant, apoptosis-inducing, anticancer activities of the plant. The aim of the present study is to examine the comparative effects of methanolic extracts ofV. albumgrown on three different host trees (locust tree, lime tree, and hedge maple tree) on H2O2-induced DNA damage in HeLa cells. Oxidative damage in mitochondrial DNA and two nuclear regions was assessed by QPCR assay. The cells were pretreated with methanolic extracts (10 μg/mL) for 48 h, followed by the treatment with 750 μM H2O2for 1 hour. DNA damage was significantly induced by H2O2while it was inhibited byV. albumextracts. All extracts completely protected against nuclear DNA damage. While the extract from lime tree or white locust tree entirely inhibited mitochondrial DNA damage, that from hedge maple tree inhibited by only 50%. These results suggest that methanolic extracts ofV. albumcan prevent oxidative DNA damage, and the activity is dependent on the host tree.

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