scholarly journals NME3 Regulates Mitochondria to Reduce ROS-Mediated Genome Instability

2020 ◽  
Vol 21 (14) ◽  
pp. 5048
Author(s):  
Chih-Wei Chen ◽  
Ning Tsao ◽  
Wei Zhang ◽  
Zee-Fen Chang
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Genome Stability ◽  
Nuclear Dna ◽  
Genome Instability ◽  
Mitochondrial Fission ◽  
Nucleoside Diphosphate Kinase ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Oxidative Stress

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses revealed that NME3 knockdown increased fragmentation of mitochondria, which in turn led to mitochondrial oxidative stress-mediated DNA single-strand breaks (SSBs) in nuclear DNA. Re-expression of wild-type NME3 or inhibition of mitochondrial fission markedly reduced SSBs and facilitated DNA repair in NME3 knockdown cells, while expression of N-terminal deleted mutant defective in mitochondrial binding had no rescue effect. We further showed that disruption of mitochondrial fusion by knockdown of NME4 or MFN1 also caused mitochondrial oxidative stress-mediated genome instability. In conclusion, the contribution of NME3 to redox-regulated genome stability lies in its function in mitochondrial fusion.

scholarly journals Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Veena Subramanian ◽  
Brian Rodemoyer ◽  
Vivek Shastri ◽  
Lene J. Rasmussen ◽  
Claus Desler ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Genome Stability ◽  
Genome Instability ◽  
Genetic Disorder ◽  
Mitochondrial Fission ◽  
Cyclin B1 ◽  
Bloom Syndrome ◽  
Dna Helicase ◽  
G1 Phase ◽  
Stress Dependent

AbstractBloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.

scholarly journals The calcilytic drug Calhex-231 ameliorates vascular hyporesponsiveness in traumatic hemorrhagic shock by inhibiting oxidative stress and mitochondrial fission

2020 ◽  
Author(s):  
Yan Lei ◽  
Xiaoyong Peng ◽  
Tao Li ◽  
Liangming Liu ◽  
Guangming Yang
Keyword(s):  
Oxidative Stress ◽  
Hemorrhagic Shock ◽  
Vascular Reactivity ◽  
Mitochondrial Fission ◽  
Blood Perfusion ◽  
Mitochondrial Fusion ◽  
Vital Organ ◽  
Animal Survival ◽  
Traumatic Hemorrhagic Shock ◽  
Mlc Phosphorylation

Abstract Background The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in non-homeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function, and investigated its relationship to oxidative stress and the mitochondrial fusion-fission pathway. Methods Rats that had been subjected to traumatic hemorrhagic shock were used as models in this study. Hypoxia-treated vascular smooth muscle cells (VSMCs) were also used. The effects of Cal on cardiovascular function, animal survival, hemodynamic parameters, and vital organ function in THS rats were observed, and the relationship to oxidative stress and mitochondrial fusion-fission was investigated. Results Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS, including the pressor response of THS rats to norepinephrine (NE), and also the contractile response of superior mesenteric arteries, mesenteric arterioles, and isolated VSMCs to NE. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation, which is the principal mechanism responsible for VSMC contraction and vascular reactivity. Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal decreased oxidative stress indexes and increased antioxidant enzyme levels in THS rats, and also reduced reactive oxygen species levels in hypoxic VSMCs. In addition, THS induced expression of mitochondrial fission proteins Drp1 and Fis1, and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1, but did not affect Mfn1 expression. In hypoxic VSMCs, Cal inhibited hypoxia-induced mitochondrial fragmentation and preserved mitochondrial morphology. Conclusions Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, due to its ability to improve hemodynamics, increase vital organ blood perfusion, and markedly prolong animal survival. These beneficial effects result from its protection of vascular function via inhibition of oxidative stress and mitochondrial fission.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

scholarly journals Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

2008 ◽  
Vol 29 (3) ◽  
pp. 794-807 ◽  
Author(s):  
Lyra M. Griffiths ◽  
Dan Swartzlander ◽  
Kellen L. Meadows ◽  
Keith D. Wilkinson ◽  
Anita H. Corbett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Intracellular Localization ◽  
Genotoxic Stress ◽  
Mitochondrial Oxidative Stress ◽  
Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

scholarly journals The mitochondrial outer-membrane location of the EXD2 exonuclease contradicts its direct role in nuclear DNA repair

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Fenna Hensen ◽  
Amandine Moretton ◽  
Selma van Esveld ◽  
Géraldine Farge ◽  
Johannes N. Spelbrink
Keyword(s):  
Dna Repair ◽  
Outer Membrane ◽  
Nuclear Dna ◽  
Mitochondrial Outer Membrane ◽  
Direct Role ◽  
Membrane Location

scholarly journals The Relevance of G-Quadruplexes for DNA Repair

2021 ◽  
Vol 22 (22) ◽  
pp. 12599
Author(s):  
Rebecca Linke ◽  
Michaela Limmer ◽  
Stefan Juranek ◽  
Annkristin Heine ◽  
Katrin Paeschke
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genome Instability ◽  
Genetic Disorders ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
G4 Dna ◽  
G Quadruplex ◽  
Repair Pathways

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

scholarly journals DYNLL1 mis-splicing is associated with replicative genome instability in SF3B1 mutant cells

2021 ◽  
Author(s):  
Annie S Tam ◽  
Shuhe Tsai ◽  
Emily Yun-Chia Chang ◽  
Veena Mathew ◽  
Alynn Shanks ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genome Stability ◽  
Genome Instability ◽  
Parp Inhibitor ◽  
Mutant Cell ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Loop Formation ◽  
Cancer Hallmarks

Genome instability is a hallmark of cancer that arises through a panoply of mechanisms driven by oncogene and tumour-suppressor gene mutations. Oncogenic mutations in the core splicing factor SF3B1 have been linked to genome instability. Since SF3B1 mutations alter the selection of thousands of 3' splice sites affecting genes across biological pathways, it is not entirely clear how they might drive genome instability. Here we confirm that while R-loop formation and associated replication stress may account for some of the SF3B1-mutant genome instability, a mechanism involving changes in gene expression also contributes. An SF3B1-H662Q mutant cell line mis-splices the 5'UTR of the DNA repair regulator DYNLL1, leading to higher DYNLL1 protein levels, mis-regulation of DNA repair pathway choice and PARP inhibitor sensitivity. Reduction of DYNLL1 protein in these cells restores genome stability. Together these data highlight how SF3B1 mutations can alter cancer hallmarks through subtle changes to the transcriptome.

scholarly journals Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

2018 ◽  
Vol 115 (30) ◽  
pp. 7777-7782 ◽  
Author(s):  
Hemanth Tummala ◽  
Arran D. Dokal ◽  
Amanda Walne ◽  
Alicia Ellison ◽  
Shirleny Cardoso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Repair ◽  
Rna Polymerase Ii ◽  
Nuclear Dna ◽  
Genome Instability ◽  
Excision Repair ◽  
Bone Marrow Failure ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Repair Defect

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients’ lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients’ LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients’ LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA–RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

scholarly journals Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Anna Ainslie ◽  
Wouter Huiting ◽  
Lara Barazzuol ◽  
Steven Bergink
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Genome Instability ◽  
Copy Number Variations ◽  
Therapeutic Interventions ◽  
Gene Copy ◽  
Protein Homeostasis ◽  
Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

Abstract 393: MCL-1 Promotes Survival and Influences Mitochondrial Dynamics in Cardiac Myocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra G Moyzis ◽  
Robert L Thomas ◽  
Jennifer Kuo ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Rapid Degradation

The BCL-2 family proteins are important regulators of mitochondrial structure and integrity. MCL-1 is an anti-apoptotic BCL-2 protein that is highly expressed in the myocardium compared to the other anti-apoptotic proteins BCL-2 and BCL-X L. Recently, we reported that MCL-1 is essential for myocardial homeostasis. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 deficient myocytes did not undergo apoptotic cell death. Instead, the cells displayed signs of mitochondrial deterioration and necrotic cell death, suggesting that MCL-1 has an additional role in maintaining mitochondrial function in cardiac myocytes. Similarly, deletion of MCL-1 in fibroblasts caused rapid mitochondrial fragmentation followed by cell death at 72 hours. Interestingly, the MCL-1 deficient fibroblasts retained cytochrome c in the mitochondria , confirming that the cells were not undergoing apoptotic cell death. We have also identified that MCL-1 localizes to the mitochondrial outer membrane (OM) and the matrix in the myocardium and that the two forms respond differently to stress. MCL-1 OM was rapidly degraded after myocardial infarction or fasting, whereas MCL-1 Matrix levels were maintained. Similarly, starvation of MEFs resulted in rapid degradation of MCL-1 OM , whereas MCL-1 Matrix showed delayed degradation. Treatment with the mitochondrial uncoupler FCCP led to rapid degradation of both forms. This suggests that the susceptibility to degradation is dependent on its localization and the nature of the stress. Our data also suggests that these two forms perform distinct functions in regulating mitochondrial morphology and survival. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission and clearance by autophagosomes. Thus, our data suggest that MCL-1 exists in two separate locations where it performs different functions. MCL-1 Matrix promotes mitochondrial fusion, which protects cells against excessive mitochondrial clearance during unfavorable conditions.

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