Mitochondrial DNA targeting and impairment by a dinuclear Ir–Pt complex that overcomes cisplatin resistance

2020 ◽  
Vol 7 (9) ◽  
pp. 1864-1871 ◽  
Author(s):  
Cheng Zhang ◽  
Ruilin Guan ◽  
Xinxing Liao ◽  
Cheng Ouyang ◽  
Jiangping Liu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Antitumor Activity ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Cell Necrosis ◽  
Mtdna Damage ◽  
Dna Targeting ◽  
Pt Complex ◽  
Strong Antitumor Activity

A dinuclear complex [(ppy)Ir(tpy)PtCl]2+ (Ir–Pt) can exhibit strong antitumor activity towards cisplatin-resistant cancer cells and induce cell necrosis via mtDNA damage and mitochondrial dysfunction.

scholarly journals Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2α-ATF4-xCT pathway

Oncotarget ◽  
2016 ◽  
Vol 7 (45) ◽  
pp. 74132-74151 ◽  
Author(s):  
Sheng-Fan Wang ◽  
Meng-Shian Chen ◽  
Yueh-Ching Chou ◽  
Yune-Fang Ueng ◽  
Pen-Hui Yin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells

scholarly journals Chronically elevated glucose compromises myocardial mitochondrial DNA integrity by alteration of mitochondrial topoisomerase function

2011 ◽  
Vol 300 (2) ◽  
pp. C338-C348 ◽  
Author(s):  
S. Medikayala ◽  
B. Piteo ◽  
X. Zhao ◽  
J. G. Edwards
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Dna Cleavage ◽  
Experimental Period ◽  
Well Being ◽  
Dna Integrity ◽  
Mtdna Damage ◽  
Mtdna Mutations ◽  
Underlying Basis ◽  
Elevated Glucose

Mitochondrial dysfunction has a significant role in the development and complications of diabetic cardiomyopathy. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) mutations are also associated with different types of cancer and neurodegenerative diseases. The goal of this study was to determine if chronically elevated glucose increase in mtDNA damage contributed to mitochondrial dysfunction and identify the underlying basis for mtDNA damage. H9c2 myotubes (a cardiac-derived cell line) were studied in the presence of 5.5, 16.5, or 33.0 mM glucose for up to 13 days. Tests of mitochondria function (Complex I and IV activity and ATP generation) were all significantly depressed by elevated media glucose. Intramitochondrial superoxide and intracellular superoxide levels were transiently increased during the experimental period. AnnexinV binding (a marker of apoptosis) was significantly increased after 7 and 13 days of high glucose. Thirteen days of elevated glucose significantly increased mtDNA damage globally and across the region encoding for the three subunits of cytochrome oxidase. Using mitochondria isolated from cells chronically exposed to elevated glucose, we observed significant increases in topoisomerase-linked DNA cleavage. Mitochondria-dependent DNA cleavage was significantly exacerbated by H2O2 and that immunoprecipitation of mitochondrial extracts with a mtTOP1 antibody significantly decreased DNA cleavage, indicating that at least part of this activity could be attributed to mtTOP1. We conclude that even mild increases in glucose presentation compromised mitochondrial function as a result of a decline in mtDNA integrity. Separate from a direct impact of oxidative stress on mtDNA, ROS-induced alteration of mitochondrial topoisomerase activity exacerbated and propagated increases in mtDNA damage. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mitochondrial DNA integrity and the well being of the myocardium.

scholarly journals Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

2013 ◽  
Vol 304 (7) ◽  
pp. H903-H915 ◽  
Author(s):  
S. Hicks ◽  
N. Labinskyy ◽  
B. Piteo ◽  
D. Laurent ◽  
J. E. Mathew ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Left Ventricle ◽  
Mitochondrial Dysfunction ◽  
Dna Cleavage ◽  
Type Ii Diabetes ◽  
Oxidant Stress ◽  
Type Ii ◽  
Mtdna Damage ◽  
Cleavage Activity ◽  
Dna Cleavage Activity

Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto-Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetes-induced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.

scholarly journals Oxidative Stress Induces Mitochondrial DNA Damage and Cytotoxicity through Independent Mechanisms in Human Cancer Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yue Han ◽  
Junjian Z. Chen
Keyword(s):  
Oxidative Stress ◽  
Prostate Cancer ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Cancer Cells ◽  
Human Cancer ◽  
Ros Production ◽  
Cell Toxicity ◽  
Normal Cells ◽  
Mtdna Damage

Intrinsic oxidative stress through increased production of reactive oxygen species (ROS) is associated with carcinogenic transformation, cell toxicity, and DNA damage. Mitochondrial DNA (mtDNA) is a natural surrogate to oxidative DNA damage. MtDNA damage results in the loss of its supercoiled structure and is readily detectable using a novel, supercoiling-sensitive real-time PCR method. Our studies have demonstrated that mtDNA damage, as measured by DNA strand breaks and copy number depletion, is very sensitive to exogenous H2O2but independent of endogenous ROS production in both prostate cancer and normal cells. In contrast, aggressive prostate cancer cells exhibit a more than 10-fold sensitivity to H2O2-induced cell toxicity than normal cells, and a cascade of secondary ROS production is a critical determinant to the differential response. We propose a new paradigm to account for different mechanisms governing cellular oxidative stress, cell toxicity, and DNA damage with important ramifications in devising new techniques and strategies in prostate cancer prevention and treatment.

scholarly journals Protection from Palmitate-Induced Mitochondrial DNA Damage Prevents from Mitochondrial Oxidative Stress, Mitochondrial Dysfunction, Apoptosis, and Impaired Insulin Signaling in Rat L6 Skeletal Muscle Cells

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 92-100 ◽  
Author(s):  
Larysa V. Yuzefovych ◽  
Viktoriya A. Solodushko ◽  
Glenn L. Wilson ◽  
Lyudmila I. Rachek
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Dna Repair ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Insulin Signaling ◽  
Mtdna Damage ◽  
L6 Myotubes ◽  
Impaired Insulin

Saturated free fatty acids have been implicated in the increase of oxidative stress, mitochondrial dysfunction, apoptosis, and insulin resistance seen in type 2 diabetes. The purpose of this study was to determine whether palmitate-induced mitochondrial DNA (mtDNA) damage contributed to increased oxidative stress, mitochondrial dysfunction, apoptosis, impaired insulin signaling, and reduced glucose uptake in skeletal muscle cells. Adenoviral vectors were used to deliver the DNA repair enzyme human 8-oxoguanine DNA glycosylase/(apurinic/apyrimidinic) lyase (hOGG1) to mitochondria in L6 myotubes. After palmitate exposure, we evaluated mtDNA damage, mitochondrial function, production of mitochondrial reactive oxygen species, apoptosis, insulin signaling pathways, and glucose uptake. Protection of mtDNA from palmitate-induced damage by overexpression of hOGG1 targeted to mitochondria significantly diminished palmitate-induced mitochondrial superoxide production, restored the decline in ATP levels, reduced activation of c-Jun N-terminal kinase (JNK) kinase, prevented cells from entering apoptosis, increased insulin-stimulated phosphorylation of serine-threonine kinase (Akt) (Ser473) and tyrosine phosphorylation of insulin receptor substrate-1, and thereby enhanced glucose transporter 4 translocation to plasma membrane, and restored insulin signaling. Addition of a specific inhibitor of JNK mimicked the effect of mitochondrial overexpression of hOGG1 and partially restored insulin sensitivity, thus confirming the involvement of mtDNA damage and subsequent increase of oxidative stress and JNK activation in insulin signaling in L6 myotubes. Our results are the first to report that mtDNA damage is the proximal cause in palmitate-induced mitochondrial dysfunction and impaired insulin signaling and provide strong evidence that targeting DNA repair enzymes into mitochondria in skeletal muscles could be a potential therapeutic treatment for insulin resistance.

scholarly journals Mitochondrial Dysfunction Due to Oxidative Mitochondrial DNA Damage Is Reduced through Cooperative Actions of Diverse Proteins

2002 ◽  
Vol 22 (12) ◽  
pp. 4086-4093 ◽  
Author(s):  
Thomas W. O'Rourke ◽  
Nicole A. Doudican ◽  
Melinda D. Mackereth ◽  
Paul W. Doetsch ◽  
Gerald S. Shadel
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Mtdna Damage ◽  
Mtdna Recombination ◽  
Mitochondrial Dna Damage ◽  
Base Excision ◽  
Enzyme Functions ◽  
Point Mutagenesis

ABSTRACT The mitochondrial genome is a significant target of exogenous and endogenous genotoxic agents; however, the determinants that govern this susceptibility and the pathways available to resist mitochondrial DNA (mtDNA) damage are not well characterized. Here we report that oxidative mtDNA damage is elevated in strains lacking Ntg1p, providing the first direct functional evidence that this mitochondrion-localized, base excision repair enzyme functions to protect mtDNA. However, ntg1 null strains did not exhibit a mitochondrial respiration-deficient (petite) phenotype, suggesting that mtDNA damage is negotiated by the cooperative actions of multiple damage resistance pathways. Null mutations in ABF2 or PIF1, two genes implicated in mtDNA maintenance and recombination, exhibit a synthetic-petite phenotype in combination with ntg1 null mutations that is accompanied by enhanced mtDNA point mutagenesis in the corresponding double-mutant strains. This phenotype was partially rescued by malonic acid, indicating that reactive oxygen species generated by the electron transport chain contribute to mitochondrial dysfunction in abf2Δ strains. In contrast, when two other genes involved in mtDNA recombination, CCE1 and NUC1, were inactivated a strong synthetic-petite phenotype was not observed, suggesting that the effects mediated by Abf2p and Pif1p are due to novel activities of these proteins other than recombination. These results document the existence of recombination-independent mechanisms in addition to base excision repair to cope with oxidative mtDNA damage in Saccharomyces cerevisiae. Such systems are likely relevant to those operating in human cells where mtDNA recombination is less prevalent, validating yeast as a model system in which to study these important issues.

Mitochondrial DNA damage triggers mitochondrial dysfunction and apoptosis in oxidant-challenged lung endothelial cells

2005 ◽  
Vol 288 (3) ◽  
pp. L530-L535 ◽  
Author(s):  
Mykhaylo Ruchko ◽  
Olena Gorodnya ◽  
Susan P. LeDoux ◽  
Mikhail F. Alexeyev ◽  
Abu-Bakr Al-Mehdi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Targeting ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Human Dna ◽  
Lung Endothelial Cells ◽  
Induced Apoptosis ◽  
Mtdna Repair

Oxidant-induced death and dysfunction of pulmonary vascular cells play important roles in the evolution of acute lung injury. In pulmonary artery endothelial cells (PAECs), oxidant-mediated damage to mitochondrial DNA (mtDNA) seems to be critical in initiating cytotoxicity inasmuch as overexpression of the mitochondrially targeted human DNA repair enzyme, human Ogg1 (hOgg1), prevents both mtDNA damage and cell death (Dobson AW, Grishko V, LeDoux SP, Kelley MR, Wilson GL, and Gillespie MN. Am J Physiol Lung Cell Mol Physiol 283: L205–L210, 2002). The mechanism by which mtDNA damage leads to PAEC death is unknown, and the present study tested the specific hypothesis that enhanced mtDNA repair suppresses PAEC mitochondrial dysfunction and apoptosis evoked by xanthine oxidase (XO). PAECs transfected either with an adenoviral vector encoding hOgg1 linked to a mitochondrial targeting sequence or with empty vector were challenged with ascending doses of XO plus hypoxanthine. Quantitative Southern blot analyses revealed that, as expected, hOgg1 overexpression suppressed XO-induced mtDNA damage. Mitochondrial overexpression of hOgg1 also suppressed the XO-mediated loss of mitochondrial membrane potential. Importantly, hOgg1 overexpression attenuated XO-induced apoptosis as detected by suppression of caspase-3 activation, by reduced DNA fragmentation, and by a blunted appearance of condensed, fragmented nuclei. These observations suggest that mtDNA damage serves as a trigger for mitochondrial dysfunction and apoptosis in XO-treated PAECs.

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