A mitochondria-targeting hetero-binuclear Ir(iii)–Pt(ii) complex induces necrosis in cisplatin-resistant tumor cells

2018 ◽  
Vol 54 (49) ◽  
pp. 6268-6271 ◽  
Author(s):  
Cheng Ouyang ◽  
Lei Chen ◽  
Thomas W. Rees ◽  
Yu Chen ◽  
Jiankang Liu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Tumor Cells ◽  
Mtdna Damage ◽  
Cellular Events ◽  
Mitochondria Targeting

A hetero-binuclear Ir(iii)–Pt(ii) complex can selectively accumulate in the mitochondria to induce mitochondrial DNA (mtDNA) damage and evoke cellular events consistent with necrosis in A549R cells.

Differential responses of AMD mitochondrial DNA haplogroups to PU–91, a mitochondria-targeting drug

Mitochondrion ◽  
2021 ◽  
Author(s):  
Andrea Bao ◽  
Sonali Nashine ◽  
Shari Atilano ◽  
Marilyn Chwa ◽  
Howard Federoff ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Differential Responses ◽  
Mitochondria Targeting

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 Mitochondria Targeting as an Effective Strategy for Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3363 ◽  
Author(s):  
Poorva Ghosh ◽  
Chantal Vidal ◽  
Sanchareeka Dey ◽  
Li Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Metastatic Tumor ◽  
Atp Production ◽  
Development Of Resistance ◽  
Mitochondrial Alterations ◽  
Mitochondria Targeting

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis

2008 ◽  
Vol 294 (2) ◽  
pp. C413-C422 ◽  
Author(s):  
Craig Ricci ◽  
Viktor Pastukh ◽  
Josh Leonard ◽  
Julio Turrens ◽  
Glenn Wilson ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Angiotensin Ii ◽  
Mitochondrial Permeability Transition ◽  
Lentiviral Vector ◽  
Mitochondrial Protein ◽  
Cellular Respiration ◽  
Second Phase ◽  
Superoxide Generation ◽  
Mtdna Damage ◽  
Mitochondrial Superoxide

Recently, it has become apparent that mitochondrial DNA (mtDNA) damage can rapidly initiate apoptosis independent of mutations, although the mechanism involved remains unclear. To elucidate this mechanism, angiotensin II-mediated apoptosis was studied in cells that were transduced with a lentiviral vector to overexpress the DNA repair enzyme 8-oxoguanine glycosylase or were treated with inhibitors known to block angiotensin II-induced mtDNA damage. Cells exhibiting angiotensin II-induced mtDNA damage showed two phases of superoxide generation, the first derived from NAD(P)H oxidase and the second of mitochondrial origin, whereas cells prevented from experiencing mtDNA damage importantly exhibited only the first phase. Furthermore, cells with mtDNA damage demonstrated impairments in mitochondrial protein expression, cellular respiration, and complex 1 activity before the onset of the second phase of oxidation. After the second phase, the mitochondrial membrane potential collapsed, cytochrome c was released, and the cells underwent apoptosis, all of which were prevented by disrupting mtDNA damage. Collectively, these data reveal a novel mechanism of apoptosis that is initiated when mtDNA damage triggers mitochondrial superoxide generation and ultimately the activation of the mitochondrial permeability transition. This novel mechanism may play an important pathological role.

scholarly journals Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human epidermal keratinocytes and melanocytes modulated by alpha-melanocyte-stimulating hormone

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 881 ◽  
Author(s):  
Markus Böhm ◽  
Helene Z. Hill
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number ◽  
Cell Types ◽  
Ultraviolet B ◽  
Epidermal Keratinocytes ◽  
Human Epidermal Keratinocytes ◽  
Mtdna Damage ◽  
Melanocyte Stimulating Hormone ◽  
Copy Numbers ◽  
Stimulating Hormone

Alpha-melanocyte-stimulating hormone (alpha-MSH) increases melanogenesis and protects from UV-induced DNA damage. However, its effect on mitochondrial DNA (mtDNA) damage is unknown. We have addressed this issue in a pilot study using human epidermal keratinocytes and melanocytes incubated with alpha-MSH and irradiated with UVB. Real-time touchdown PCR was used to quantify total and deleted mtDNA. The deletion detected encompassed the common deletion but was more sensitive to detection. There were 4.4 times more mtDNA copies in keratinocytes than in melanocytes. Irradiation alone did not affect copy numbers. Alpha-MSH slightly increased copy numbers in both cell types in the absence of UVB and caused a similar small decrease in copy number with dose in both cell types. Deleted copies were nearly twice as frequent in keratinocytes as in melanocytes. Alpha-MSH reduced the frequency of deleted copies by half in keratinocytes but not in melanocytes. UVB dose dependently led to an increase in the deleted copy number in alpha-MSH-treated melanocytes. UVB irradiation had little effect on deleted copy number in alpha-MSH-treated keratinocytes. In summary, alpha-MSH enhances mtDNA damage in melanocytes presumably by increased melanogenesis, while α-MSH is protective in keratinocytes, the more so in the absence of irradiation.

Amyloid-β Oligomers-induced Mitochondrial DNA Repair Impairment Contributes to Altered Human Neural Stem Cell Differentiation

2019 ◽  
Vol 16 (10) ◽  
pp. 934-949 ◽  
Author(s):  
Jing Lu ◽  
Yi Li ◽  
Cristiana Mollinari ◽  
Enrico Garaci ◽  
Daniela Merlo ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Neural Stem Cell ◽  
Stem Cell Differentiation ◽  
Ros Production ◽  
End Joining ◽  
Vitro Assay ◽  
Mtdna Damage ◽  
Mtdna Repair

Background: Amyloid-β42 oligomers (Aβ42O), the proximate effectors of neurotoxicity observed in Alzheimer’s disease (AD), can induce mitochondrial oxidative stress and impair mitochondrial function besides causing mitochondrial DNA (mtDNA) damage. Aβ42O also regulate the proliferative and differentiative properties of stem cells. Objective: We aimed to study whether Aβ42O-induced mtDNA damage is involved in the regulation of stem cell differentiation. Method: Human iPSCs-derived neural stem cell (NSC) was applied to investigate the effect of Aβ42O on reactive oxygen species (ROS) production and DNA damage using mitoSOX staining and long-range PCR lesion assay, respectively. mtDNA repair activity was measured by non-homologous end joining (NHEJ) in vitro assay using mitochondria isolates and the expression and localization of NHEJ components were determined by Western blot and immunofluorescence assay. The expressions of Tuj-1 and GFAP, detected by immunofluorescence and qPCR, respectively, were examined as an index of neurons and astrocytes production. Results: We show that in NSC Aβ42O treatment induces ROS production and mtDNA damage and impairs DNA end joining activity. NHEJ components, such as Ku70/80, DNA-PKcs, and XRCC4, are localized in mitochondria and silencing of XRCC4 significantly exacerbates the effect of Aβ42O on mtDNA integrity. On the contrary, pre-treatment with Phytic Acid (IP6), which specifically stimulates DNA-PK-dependent end-joining, inhibits Aβ42O-induced mtDNA damage and neuronal differentiation alteration. Conclusion: Aβ42O-induced mtDNA repair impairment may change cell fate thus shifting human NSC differentiation toward an astrocytic lineage. Repair stimulation counteracts Aβ42O neurotoxicity, suggesting mtDNA repair pathway as a potential target for the treatment of neurodegenerative disorders like AD.

scholarly journals Type II diabetes increases myocardial mitochondrial DNA (mtDNA) damage by altered mitochondrial topoisomerase function

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
John Grenville Edwards ◽  
Brian Piteo ◽  
Dimitri Laurent ◽  
Maria Mitry ◽  
Steven Hicks
Keyword(s):  
Mitochondrial Dna ◽  
Type Ii Diabetes ◽  
Type Ii ◽  
Mtdna Damage

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.

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.

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