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Journal articles on the topic 'Mitochondrial derivative'
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1
Shin, Weon Sup, Soon Ki Park, Peter Verwilst, et al. "Targeted combinational therapy inducing mitochondrial dysfunction." Chemical Communications 53, no. 7 (2017): 1281–84. http://dx.doi.org/10.1039/c6cc08977a.
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Bernstein, Steven H., Bin Lin, Shannon Hilchey, et al. "The Triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid and Its Derivatives Inhibit Mitochondrial Lon Protease Activity: A Potential Novel Pathway for the Induction of Lymphoma Cell Death." Blood 114, no. 22 (2009): 414. http://dx.doi.org/10.1182/blood.v114.22.414.414.
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Abstract Abstract 414 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its C(28) imidazole and methylester derivatives are novel oleanane triterpenoids exhibiting promise as both therapeutic and preventative agents for cancer. We have previously shown that these synthetic triterpenoids promote lymphoma cell death through a novel mitochondria-mediated mechanism whereby mitochondrial protein thiols are modified resulting in the formation of mitochondrial protein aggregates leading to apoptotic cell death (Cancer Res. 2007; 67:4). As mitochondrial Lon is a critical quality control protease that prevents the toxic accumulation and aggregation of damaged mitochondrial proteins we hypothesized that one effect of the triterpenoids might be to inhibit Lon-mediated proteolysis. Herein we show that CDDO and its derivatives inhibit purified Lon protease. In particular, the imidazole and methylester derivatives of CDDO (CDDO-Im and CDDO-Me) are more effective inhibitors of Lon than CDDO. Interestingly, these derivatives are also more potent inducers of lymphoma cell death than CDDO. We also show that CDDO-Me inhibits cellular mitochondrial Lon, as determined by its ability to inhibit the degradation of the Mitochondrial Transcription Factor A (TFAM), an endogenous Lon protein substrate. To exclude the possibility that the triterpenoid mediated inhibition of TFAM degradation is mediated by the cytoplasmic proteasome, we show that the triterpenoids have no effect on proteasome-mediated proteolysis. To determine the mechanism through which the triterpenoids block Lon activity, we next used a biotinylated-CDDO derivative and showed that this derivative forms adducts with Lon, suggesting that the triterpenoids directly inhibit the protease in cells. In contrast, the biotinylated-CDDO derivative did not form adducts with other proteins, such as the mitochondrial ClpP protease, TFAM, or the endoplasmic reticulum protein BiP, suggesting a level of specificity for triterpenoid adduct formation. Indeed, the formation of protein adducts with Lon is consistent with the fact that the triterpenoids contain a Michael Addition moiety which allows it to form adducts with both protein and non-protein thiols. Consistent with the inhibitory effects of the triterpenoids on mitochondrial Lon protease activity, CDDO-treated lymphoma cells exhibit striking electron dense inclusions within mitochondria, but not the cytosol or other cellular compartments. Similar inclusions within mitochondria are also seen in a Lon knockdown cell line, in which a short hairpin RNA targeting Lon mRNA is inducibly expressed in LS174 colon cancer cells upon treatment with doxycycline. This finding supports the notion that the CDDO-induced inclusions are due, in part, to inhibition of Lon protease activity. Furthermore, we show that Lon protein expression levels are higher in both malignant lymphoma cell lines and patient derived biopsy specimens, as compared to that seen in resting or activated normal B cells. Taken together, these results suggest that; (a) the mitochondrial ATP-dependent Lon protease is a new target of synthetic triterpenoids, and; (b) Lon may be a novel and viable target for cancer therapeutics. Supported by an NCI SPORE grant in lymphoma 1P50 CA130805. Disclosures: Bernstein: millenium: Consultancy; genentech: Consultancy, Speakers Bureau; enzon: Consultancy.
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McCormick, A. Louise, Vanessa L. Smith, Dar Chow, and Edward S. Mocarski. "Disruption of Mitochondrial Networks by the Human Cytomegalovirus UL37 Gene Product Viral Mitochondrion-Localized Inhibitor of Apoptosis." Journal of Virology 77, no. 1 (2003): 631–41. http://dx.doi.org/10.1128/jvi.77.1.631-641.2003.
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ABSTRACT By 24 h after infection with human cytomegalovirus, the reticular mitochondrial network characteristic of uninfected fibroblasts was disrupted as mitochondria became punctate and dispersed. These alterations were associated with expression of the immediate-early (α) antiapoptotic UL37x1 gene product viral mitochondrion-localized inhibitor of apoptosis (vMIA). Similar alterations in mitochondrial morphology were induced directly by vMIA in transfected cells. A 68-amino-acid antiapoptotic derivative of vMIA containing the mitochondrial localization and antiapoptotic domains also induced disruption, whereas a mutant lacking the antiapoptotic domain failed to cause disruption. These data suggest that the fission and/or fusion process that normally controls mitochondrial networks is altered by vMIA. Mitochondrial fission has been implicated in the induction of apoptosis and vMIA-mediated inhibition of apoptosis may occur subsequent to this event.
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Sarti, Paolo, Elena Forte, Alessandro Giuffrè, Daniela Mastronicola, Maria Chiara Magnifico, and Marzia Arese. "The Chemical Interplay between Nitric Oxide and Mitochondrial CytochromecOxidase: Reactions, Effectors and Pathophysiology." International Journal of Cell Biology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/571067.
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Nitric oxide (NO) reacts with Complex I and cytochromecoxidase (CcOX, Complex IV), inducing detrimental or cytoprotective effects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX-NO2 −, PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying different persistency and O2competitiveness. In the mitochondrion, during turnover with O2, one pathway prevails over the other one depending on NO, cytochromec2+and O2concentration. High cytochromec2+, and low O2proved to be crucial in favoring CcOX nitrosylation, whereas under-standardcell-culture conditions formation of the nitrite derivative prevails. All together, these findings suggest that NO can modulate physiologically the mitochondrial respiratory/OXPHOS efficiency, eventually being converted to nitrite by CcOX, without cell detrimental effects. It is worthy to point out that nitrite, far from being a simple oxidation byproduct, represents a source of NO particularly important in view of the NO cell homeostasis, the NO production depends on the NO synthases whose activity is controlled by different stimuli/effectors; relevant to its bioavailability, NO is also produced by recycling cell/body nitrite. Bioenergetic parameters, such as mitochondrialΔΨ, lactate, and ATP production, have been assayed in several cell lines, in the presence of endogenous or exogenous NO and the evidence collected suggests a crucial interplay between CcOX and NO with important energetic implications.
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Dubinin, Mikhail V., Alena A. Semenova, Darya A. Nedopekina, Eldar V. Davletshin, Anna Yu Spivak, and Konstantin N. Belosludtsev. "Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation." Membranes 11, no. 5 (2021): 352. http://dx.doi.org/10.3390/membranes11050352.
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This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.
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Blázquez-Moraleja, Alberto, Ines Sáenz-de-Santa María, María D. Chiara, et al. "Shedding light on the mitochondrial matrix through a functional membrane transporter." Chemical Science 11, no. 4 (2020): 1052–65. http://dx.doi.org/10.1039/c9sc04852a.
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Aghvami, Marjan, Jalal Pourahmad, Afshin Zarghi, et al. "A Newly Synthetized Ferrocenyl Derivative Selectively Induces Apoptosis in ALL Lymphocytes through Mitochondrial Estrogen Receptors." Anti-Cancer Agents in Medicinal Chemistry 18, no. 7 (2018): 1032–43. http://dx.doi.org/10.2174/1871520618666171206112446.
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Background: Estrogens, as the main female steroid hormones have multiple proven effects on reproductive and non- reproductive systems. Expression of ERα and ERβ, two dominant estrogen receptors, in peripheral blood mononuclear cells in certain B-cell malignancies and the existence of estrogens receptors on mitochondria is open to question that estrogen likely has an impact on the cancerous lymphocytes life span. Acute Lymphoblastic Leukemia (ALL) is the frequent pediatric malignity which is recurrent and hardly curable in many cases. The malignant cells are generally resistant to apoptosis caused the severe lymphocytes accumulation in the peripheral blood. Methods: By focusing on mitochondria as a life/death center of the cell; in the current research we compared cytotoxicity effects of a new ferrocenyl derivative with raloxifene as well-known SERMs considering the apoptotic process and survival of cancerous lymphocytes. Results: We demonstrated that both ferrocenyl derivative and raloxifene could cause mitochondrial lesion and initiate the apoptosis process by caspase activation and cytochrome c release. Conclusion: In brief, the ferrocenyl derivative could induce estrogen-related selective apoptosis on cancerous lymphocytes by affecting mitochondrial receptors.
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FONSECA-BERZAL, CRISTINA, CRISTIANE FRANÇA DA SILVA, RUBEM F. S. MENNA-BARRETO, et al. "Biological approaches to characterize the mode of action of two 5-nitroindazolinone prototypes on Trypanosoma cruzi bloodstream trypomastigotes." Parasitology 143, no. 11 (2016): 1469–78. http://dx.doi.org/10.1017/s0031182016001098.
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SUMMARYThe phenotypic activity of two 5-nitroindazolinones, i.e. 2-benzyl-1-propyl (22) and 2-benzyl-1-butyl (24) derivatives, previously proposed as anti-Trypanosoma cruzi prototypes, was presently assayed on bloodstream trypomastigotes (BT) of the moderately drug-resistant Y strain. Further exploration of putative targets and cellular mechanisms involved in their activity was also carried out. Therefore, transmission electron microscopy, high-resolution respirometry and flow cytometry procedures were performed on BT treated for up to 24 h with the respective EC50 value of each derivative. Results demonstrated that although 22 and 24 were not as active as benznidazole in this in vitro assay on BT, both compounds triggered important damages in T. cruzi that lead to the parasite death. Ultrastructural alterations included shedding events, detachment of plasma membrane and nuclear envelope, loss of mitochondrial integrity, besides the occurrence of a large number of intracellular vesicles and profiles of endoplasmic reticulum surrounding cytoplasmic organelles such as mitochondrion. Moreover, both derivatives affected mitochondrion leading to this organelle dysfunction, as reflected by the inhibition in oxygen consumption and the loss of mitochondrial membrane potential. Altogether, the findings exposed in the present study propose autophagic processes and mitochondrial machinery as part of the mode of action of both 5-nitroindazolinones 22 and 24 on T. cruzi trypomastigotes.
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Miniero, Daniela Valeria, Anna Spagnoletta, Nicola Gambacorta, et al. "The Interaction of Hemin, a Porphyrin Derivative, with the Purified Rat Brain 2-Oxoglutarate Carrier." Biomolecules 11, no. 8 (2021): 1175. http://dx.doi.org/10.3390/biom11081175.
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The mitochondrial 2-oxoglutarate carrier (OGC), isolated and purified from rat brain mitochondria, was reconstituted into proteoliposomes to study the interaction with hemin, a porphyrin derivative, which may result from the breakdown of heme-containing proteins and plays a key role in several metabolic pathways. By kinetic approaches, on the basis of the single binding centre gated pore mechanism, we analyzed the effect of hemin on the transport rate of OGC in uptake and efflux experiments in proteoliposomes reconstituted in the presence of the substrate 2-oxoglutarate. Overall, our experimental data fit the hypothesis that hemin operates a competitive inhibition in the 0.5–10 µM concentration range. As a consequence of the OGC inhibition, the malate/aspartate shuttle might be impaired, causing an alteration of mitochondrial function. Hence, considering that the metabolism of porphyrins implies both cytoplasmic and mitochondrial processes, OGC may participate in the regulation of porphyrin derivatives availability and the related metabolic pathways that depend on them (such as oxidative phosphorylation and apoptosis). For the sake of clarity, a simplified model based on induced-fit molecular docking supported the in vitro transport assays findings that hemin was as good as 2-oxoglutarate to bind the carrier by engaging specific ionic hydrogen bond interactions with a number of key residues known for participating in the similarly located mitochondrial carrier substrate binding site.
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Sheng, Li-Xin, Jiang-Yu Zhang, Li Li, Xiao Xie, Xiao-An Wen, and Ke-Guang Cheng. "Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway." Biomolecules 10, no. 1 (2020): 123. http://dx.doi.org/10.3390/biom10010123.
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In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; up regulation of Apaf-1, Bax, and cytochrome c; down regulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner.
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Kloepping, Kyle C., Alora S. Kraus, Devin K. Hedlund, et al. "Triphenylphosphonium derivatives disrupt metabolism and inhibit melanoma growth in vivo when delivered via a thermosensitive hydrogel." PLOS ONE 15, no. 12 (2020): e0244540. http://dx.doi.org/10.1371/journal.pone.0244540.
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Despite dramatic improvements in outcomes arising from the introduction of targeted therapies and immunotherapies, metastatic melanoma is a highly resistant form of cancer with 5 year survival rates of <35%. Drug resistance is frequently reported to be associated with changes in oxidative metabolism that lead to malignancy that is non-responsive to current treatments. The current report demonstrates that triphenylphosphonium(TPP)-based lipophilic cations can be utilized to induce cytotoxicity in pre-clinical models of malignant melanoma by disrupting mitochondrial metabolism. In vitro experiments demonstrated that TPP-derivatives modified with aliphatic side chains accumulated in melanoma cell mitochondria; disrupted mitochondrial metabolism; led to increases in steady-state levels of reactive oxygen species; decreased total glutathione; increased the fraction of glutathione disulfide; and caused cell killing by a thiol-dependent process that could be rescued by N-acetylcysteine. Furthermore, TPP-derivative-induced melanoma toxicity was enhanced by glutathione depletion (using buthionine sulfoximine) as well as inhibition of thioredoxin reductase (using auranofin). In addition, there was a structure-activity relationship between the aliphatic side-chain length of TPP-derivatives (5–16 carbons), where longer carbon chains increased melanoma cell metabolic disruption and cell killing. In vivo bio-distribution experiments showed that intratumoral administration of a C14-TPP-derivative (12-carbon aliphatic chain), using a slow-release thermosensitive hydrogel as a delivery vehicle, localized the drug at the melanoma tumor site. There, it was observed to persist and decrease the growth rate of melanoma tumors. These results demonstrate that TPP-derivatives selectively induce thiol-dependent metabolic oxidative stress and cell killing in malignant melanoma and support the hypothesis that a hydrogel-based TPP-derivative delivery system could represent a therapeutic drug-delivery strategy for melanoma.
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Piga, Rosaria, Yuji Naito, Satoshi Kokura, Osamu Handa, and Toshikazu Yoshikawa. "Protective effect of serotonin derivatives on glucose-induced damage in PC12 rat pheochromocytoma cells." British Journal of Nutrition 103, no. 1 (2009): 25–31. http://dx.doi.org/10.1017/s0007114509991486.
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Oxidative damage is believed to be associated with ageing, cancer and several degenerative diseases. Previous reports have shown that safflower-seed extract and its major antioxidant constituents, serotonin hydroxycinnamic amides, possess a powerful free radical-scavenging and antioxidative activity, paying particular attention to atherosclerotic reactive oxygen species (ROS)-related dysfunctions. In the present report, we examined a still unknown cell-based mechanism of serotonin derivatives against ROS-related neuronal damage, phenomena that represent a crucial event in neurodegenerative diseases. Serotonin derivatives N-(p-coumaroyl)serotonin and N-feruloylserotonin exerted a protective effect on high glucose-induced cell death, inhibited the activation of caspase-3 which represents the last and crucial step within the cascade of events leading to apoptosis, and inhibited the overproduction of the mitochondrial superoxide, which represents the most dangerous radical produced by hyperglycaemia, by acting as scavengers of the superoxide radical. In addition, serotonin derivative concentration inside the cells and inside the mitochondria was increased in a time-dependent manner. Since recent studies support the assertion that mitochondrial dysfunctions related to oxidative damage are the major contributors to neurodegenerative diseases, these preliminary cell-based results identify a mitochondria-targeted antioxidant property of serotonin derivatives that could represent a novel therapeutic approach against the neuronal disorders and complications related to ROS.
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Sarnyai, Farkas, Timea Szekerczés, Miklós Csala, et al. "BGP-15 Protects Mitochondria in Acute, Acetaminophen Overdose Induced Liver Injury." Pathology & Oncology Research 26, no. 3 (2019): 1797–803. http://dx.doi.org/10.1007/s12253-019-00721-1.
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Abstract Acetaminophen (APAP) induced hepatotoxicity involves activation of c-Jun amino-terminal kinase (JNK), mitochondrial damage and ER stress. BGP-15, a hydroximic acid derivative, has been reported to have hepatoprotective effects in APAP overdose induced liver damage. Effect of BGP-15 was further investigated on mitochondria in APAP-overdose induced acute liver injury in mice. We found that BGP-15 efficiently preserved mitochondrial morphology, and it caused a marked decrease in the number of damaged mitochondria. Attenuation of mitochondrial damage by BGP-15 is supported by immunohistochemistry as the TOMM20 label and the co-localized autophagy markers detected in the livers of APAP-treated mice were markedly reduced upon BGP-15 administration. This effect, along with the observed prevention of JNK activation likely contribute to the mitochondrial protective action of BGP-15.
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Chou, Yin-Chen, Chia-Wei Chen, Yuan-Yeh Kuo, Liang-In Lin, and Chung-Yi Hu. "Botanical Alkyl Hydroquinone Derivative HQ17(3) Induces Calcium-Associated Mitochondrial Damage and Mitophagy to Exert Ctotoxicity to Philadelphila Chromosome(+) ALL Cells." Blood 132, Supplement 1 (2018): 5800. http://dx.doi.org/10.1182/blood-2018-99-120307.
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Abstract Introduction: Acute lymphoblastic leukemias (ALLs) harboring t(9;22)(Ph+-ALL) are very high risk (VHR) ALL displaying poor clinical outcome irrespective of intensive chemotherapies plus tyrosine kinase inhibitor (TKI) treatment. HQ17(3)[10'(Z),13'(E),15'(E)-heptadecatrienyl hydroquinone] isolated from sap of the lacquer tree showed rapid (within 24hrs) and potent cytotoxic effect at micromolar concentration on several ALL cell lines, including Imatinib-refractory Ph+-ALL SUP-B15 cells, but spared normal PB leukocytes, and showed nontoxic in experimental rats after 28-day injection. Therefore HQ17(3) presents as a potential anti-leukemic agents and provide a platform for exploring anti-leukemic adjuvants. Our previous study showed HQ17(3)-induced rapid cell demise, characterized by oxidative stress, mitochondrial membrane potential disturbance, loss of membrane integrity, and nuclear DNA fragmentation. HQ17(3)-induced cell death is a caspase-independent program, and is different from the RIP1-mediated controlled necroptosis since both pan-caspase inhibitor and RIP-1 inhihitor failed to protect SUP-B15 cells from death. The ER stress markers (chaperon Grp78 and phosphorylated-eIF2α) were up-regulated as early as 5hrs after HQ17(3) treatment. Here we aim to illustrate the characters of the HQ17(3)-induced non-classical death on Ph+-SUP-B15 cells, focus on ER stress-associated mitochondrial Ca2+ homeostasis. Methods: Cell death and changes of mitochondria in response to HQ17(3) w/wo inhibitors were analyzed. Cells were stained by Annexin V/PI and analyzed by flow cytometry for cell death. Mitochondria mass, mitochondrial Ca2+ accumulation was detected by fluorescent Mitotracker Green and Rhod-2 probes, respectively. Mitochondrial superoxide was measured by Mitosox stain. Western blot analysis was used to analyze MFN1/2, OPA1 (mitochondrial markers). Nuclear accumulation of apoptosis inducing factor (AIF), co-localization of mitochondrial COX-IV and LC3-II (mitophagy) were revealed by immunofluorescence stain and confocal microscopy. Results: We showed mitochondrial Ca2+ accumulation at the early time when ER stress occurred (Fig 1), accompanied by mitochondrial superoxide elevation, followed by loss of mitochondrial membrane potential (MMP) and nuclear translocation of apoptosis-inducing factor (AIF). HQ17(3) treatment lead to decreased mitochondrial proteins MFN1/2 and OPA1, while Mitotracker Green stain showed significant loss of mitochondrial mass preceded cell death, indicating damaged mitochondria underwent fission followed by mitophagy. Immunofluorescence stain showed evidence of mitophagy (COX IV and LC3B co-localization). Calpain-1 inhibitor PD150606 blocked AIF nuclear translocation but only slightly reduced the HQ17(3)-induced cell death (Fig 2). Further, Ca2+ chelator Bapta-AM prevented mitochondrial superoxide production, MMP loss, mitophagy (Fig 3), and rescued cell death (Fig 1) more effectively. Conclusion: In Ph+-ALL SUP-B15 cells, HQ17(3) induce ER stress by yet-defined mechanism, this mobilizes Ca2+ to mitochondria and acts in multi-facet: a) results in AIF cleavage and translocation to mediate nuclear chromatin fragmentation, b) Ca2+-overload leads to oxidative stress and perturbs mitochondria integrity, c) damaged mitochondria trigger extensive mitophagy and cell death ensues. Therefore, agents that help elicit similar intricate effector network associated with ER/mitochondria stress will have potential to be adjuvants in aiding control of the Ph+ VHR-ALL cells refractory to conventional chemotherapies and TKI regime. Disclosures No relevant conflicts of interest to declare.
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Uzhachenko, Roman, Anil Shanker, and Geneviève Dupont. "Computational properties of mitochondria in T cell activation and fate." Open Biology 6, no. 11 (2016): 160192. http://dx.doi.org/10.1098/rsob.160192.
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In this article, we review how mitochondrial Ca 2+ transport (mitochondrial Ca 2+ uptake and Na + /Ca 2+ exchange) is involved in T cell biology, including activation and differentiation through shaping cellular Ca 2+ signals. Based on recent observations, we propose that the Ca 2+ crosstalk between mitochondria, endoplasmic reticulum and cytoplasm may form a proportional–integral–derivative (PID) controller. This PID mechanism (which is well known in engineering) could be responsible for computing cellular decisions. In addition, we point out the importance of analogue and digital signal processing in T cell life and implication of mitochondrial Ca 2+ transport in this process.
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Iaubasarova, Iliuza R., Ljudmila S. Khailova, Alexander M. Firsov, et al. "The mitochondria-targeted derivative of the classical uncoupler of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone is an effective mitochondrial recoupler." PLOS ONE 15, no. 12 (2020): e0244499. http://dx.doi.org/10.1371/journal.pone.0244499.
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The synthesis of a mitochondria-targeted derivative of the classical mitochondrial uncoupler carbonyl cyanide-m-chlorophenylhydrazone (CCCP) by alkoxy substitution of CCCP with n-decyl(triphenyl)phosphonium cation yielded mitoCCCP, which was able to inhibit the uncoupling action of CCCP, tyrphostin A9 and niclosamide on rat liver mitochondria, but not that of 2,4-dinitrophenol, at a concentration of 1–2 μM. MitoCCCP did not uncouple mitochondria by itself at these concentrations, although it exhibited uncoupling action at tens of micromolar concentrations. Thus, mitoCCCP appeared to be a more effective mitochondrial recoupler than 6-ketocholestanol. Both mitoCCCP and 6-ketocholestanol did not inhibit the protonophoric activity of CCCP in artificial bilayer lipid membranes, which might compromise the simple proton-shuttling mechanism of the uncoupling activity on mitochondria.
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Samudio, Ismael, Marina Konopleva, Numsen Hail, et al. "2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione to Induce Apoptosis in Pancreatic Cancer." Journal of Biological Chemistry 280, no. 43 (2005): 36273–82. http://dx.doi.org/10.1074/jbc.m507518200.
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Surgical resection is the only curative strategy for pancreatic cancer (PC). Unfortunately, >80% of pancreatic cancer patients bear inoperable, locally advanced, chemoresistant tumors demonstrating the urgent need for development of novel therapeutic approaches to treat this disease. Here we report that the synthetic triterpenoid 2-cyano-3,12 dioxooleana-1,9 dien-28-imidazolide (CDDO-Im) antagonizes PC cell growth by inducing apoptosis at submicromolar concentrations. Notably, we demonstrate for the first time that the cytotoxicity of CDDO-Im is accompanied by the rapid and selective depletion of mitochondrial glutathione that results in accumulation of reactive oxygen species, oxidation of the cellular glutathione pool, loss of mitochondrial membrane potential, and phosphatidylserine externalization. The parent compound CDDO as well as the methyl ester of CDDO also depleted mitochondrial glutathione, demonstrating that this effect is mediated by the triterpenoid nucleus of these agents. Cotreatment with sulfhydryl nucleophiles completely prevented apoptosis and loss of viability induced by CDDO-Im, whereas alkylation of intracellular thiols by diethylmaleate or cotreatment with dithiothreitol decreased the accumulation of a biotinylated derivative of CDDO, TP-301, in PC cells, suggesting that intracellular reduced thiols are functional targets of the electrophilic triterpenoid nucleus of CDDO and its derivatives. In conclusion, our report is the first to identify mitochondrial glutathione as a target of CDDO and its derivatives and demonstrates that depletion of this antioxidant in the mitochondria is an effective strategy to induce cell death in PC cells. These results suggest that CDDO and its derivatives may offer a clinical benefit for the treatment of PC.
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Quijano, Celia, Laura Castro, Gonzalo Peluffo, Valeria Valez, and Rafael Radi. "Enhanced mitochondrial superoxide in hyperglycemic endothelial cells: direct measurements and formation of hydrogen peroxide and peroxynitrite." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 6 (2007): H3404—H3414. http://dx.doi.org/10.1152/ajpheart.00761.2007.
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Hyperglycemic challenge to bovine aortic endothelial cells (BAECs) increases oxidant formation and cell damage that are abolished by MnSOD overexpression, implying mitochondrial superoxide (O2•−) as a central mediator. However, mitochondrial O2•− and its steady-state concentrations have not been measured directly yet. Therefore, we aimed to detect and quantify O2•− through different techniques, along with the oxidants derived from it. Mitochondrial aconitase, a sensitive target of O2•−, was inactivated 60% in BAECs incubated in 30 mM glucose (hyperglycemic condition) with respect to cells incubated in 5 mM glucose (normoglycemic condition). Under hyperglycemic conditions, increased oxidation of the mitochondrially targeted hydroethidine derivative (MitoSOX) to hydroxyethidium, the product of the reaction with O2•−, could be specifically detected. An 8.8-fold increase in mitochondrial O2•− steady-state concentration (to 250 pM) and formation rate (to 6 μM/s) was estimated. Superoxide formation increased the intracellular concentration of both hydrogen peroxide, measured as 3-amino-2,4,5-triazole-mediated inactivation of catalase, and nitric oxide-derived oxidants (i.e., peroxynitrite), evidenced by immunochemical detection of 3-nitrotyrosine. Oxidant formation was further evaluated by chloromethyl dichlorodihydrofluorescein (CM-H2DCF) oxidation. Exposure to hyperglycemic conditions triggered the oxidation of CM-H2DCF and was significantly reduced by pharmacological agents that lower the mitochondrial membrane potential, inhibit electron transport (i.e., myxothiazol), and scavenge mitochondrial oxidants (i.e., MitoQ). In BAECs devoid of mitochondria (rho0 cells), hyperglycemic conditions did not increase CM-H2DCF oxidation. Mitochondrial O2•− formation in hyperglycemic conditions was associated with increased glucose metabolization in the Krebs cycle and hyperpolarization of the mitochondrial membrane.
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Kamiya, Naohiro, Atsushi Kubota, Yumiko Iwase, Kouichi Sekiya, Masaru Ubasawa, and Satoshi Yuasa. "Antiviral Activities of MCC-478, a Novel and Specific Inhibitor of Hepatitis B Virus." Antimicrobial Agents and Chemotherapy 46, no. 9 (2002): 2872–77. http://dx.doi.org/10.1128/aac.46.9.2872-2877.2002.
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ABSTRACT MCC-478 is a newly synthesized 2-amino-6-arylthio-9-phosphonomethoxyethylpurine bis(2,2,2-trifluoroethyl) ester derivative. MCC-478 showed a substantially higher (ca. 80-fold) anti-hepatitis B virus (HBV) activity than that of lamivudine, despite no significant anti-human immunodeficiency virus activity. Since the bis(2,2,2-trifluoroethyl) ester group was used to improve the oral bioavailability of the phosphonomethoxyethylpurine derivatives, two monoester derivatives and one phosphonic acid derivative were also evaluated. It was suggested that these hydrolyzed derivatives, which appeared in animals given MCC-478, have enough anti-HBV activity to contribute to efficacy in vivo. Furthermore, no apparent cytotoxic effects or reductions of mitochondrial DNA content by MCC-478 and its derivatives were observed. These results indicated that MCC-478 may be a new promising anti-HBV agent.
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Belyaeva, Veronika S., Yulia V. Stepenko, Igor I. Lyubimov, et al. "Non-hematopoietic erythropoietin-derived peptides for atheroprotection and treatment of cardiovascular diseases." Research Results in Pharmacology 6, no. 3 (2020): 75–86. http://dx.doi.org/10.3897/rrpharmacology.6.58891.
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Relevance: Cardiovascular diseases continue to be the leading cause of premature adult death. Lipid profile and atherogenesis: Dislipidaemia leads to subsequent lipid accumulation and migration of immunocompetent cells into the vessel intima. Macrophages accumulate cholesterol forming foam cells – the morphological substrate of atherosclerosis in its initial stage. Inflammation and atherogenesis: Pro-inflammatory factors provoke oxidative stress, vascular wall damage and foam cells formation. Endothelial and mitochondrial dysfunction in the development of atherosclerosis: Endothelial mitochondria are some of the organelles most sensitive to oxidative stress. Damaged mitochondria produce excess superoxide and H2O2, which are the main factors of intracellular damage, further increasing endothelial dysfunction. Short non-hematopoietic erythropoietin-based peptides as innovative atheroprotectors: Research in recent decades has shown that erythropoietin has a high cytoprotective activity, which is mainly associated with exposure to the mitochondrial link and has been confirmed in various experimental models. There is also a short-chain derivative, the 11-amino acid pyroglutamate helix B surface peptide (PHBSP), which selectively binds to the erythropoietin heterodymic receptor and reproduces its cytoprotective properties. This indicates the promising use of short-chain derivatives of erythropoietin for the treatment and prevention of atherosclerotic vascular injury. In the future, it is planned to study the PHBSP derivatives, the modification of which consists in adding RGD and PGP tripeptides with antiaggregant properties to the original 11-member peptide.
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ROSSI, Luigia, Sonja SERAFINI, Giuditta F. SCHIAVANO, et al. "Metabolism, mitochondrial uptake and toxicity of 2′,3′-dideoxycytidine." Biochemical Journal 344, no. 3 (1999): 915–20. http://dx.doi.org/10.1042/bj3440915.
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2ʹ,3ʹ-Dideoxycytidine (ddCyd) is a prescription anti-retroviral drug that causes mitochondrial toxicity and peripheral neuropathy. ddCyd is actively phosphorylated by cytosolic deoxycytidine kinase and nucleoside (di)phosphate kinase to the 5ʹ-triphosphate derivative. However, 2ʹ,3ʹ-dideoxycytidine 5ʹ-diphosphocholine (ddCDP-choline) was also found in human cells incubated with ddCyd. In this paper we show that ddCDP-choline is produced from dideoxyCTP (ddCTP) and phosphocholine by phosphocholine cytidylyltransferase. dCTP and CTP appear to activate this synthesis in a concentration-dependent manner. Although ddCTP and ddCDP-choline can both enter the mitochondria, ddCDP-choline uptake is more efficient than ddCTP uptake. These data suggest that ddCDP- choline is the ddCyd metabolite that is probably responsible for mitochondrial toxicity. The uptake of ddCTP and ddCDP-choline by mitochondria is inhibited by 3.0 mM L-carnitine in the cell-free system investigated; when added to U937 cells grown in the presence of 0.25 μM ddCyd, 3.0 mM L-carnitine partially abrogated the mitochondrial toxicity of ddCyd.
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Claisse, Maurice L., Magdalena Boguta, and Włodzimierz Zagórski. "Translational readthrough of a termination codon in the yeast mitochondrial mRNA VAR1 as a result of mutation in the release factor mRF1." Acta Biochimica Polonica 52, no. 1 (2005): 129–37. http://dx.doi.org/10.18388/abp.2005_3497.
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Yeast mitochondrial DNA codes for eight major polypeptides. Translation of he mitochondrially encoded polypeptides in strains with mutated mitochondrial release factor, mRF1, was found to result in the synthesis of a novel protein, V2. Different mrf1 alleles were associated with different efficiency of V2p synthesis. Translation of V2p was enhanced by paromomycin. Comparative analysis of peptides resulting from protease digestion indicated that V2p is a derivative of Var1p. According to our hypothesis, V2p represents a readthrough product of the natural stop codon in VAR1 mRNA.
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Manshouri, Taghi, Subbarao V. Kala, Faramarz Ashoori, et al. "Comparison of Uptake and Intracellular Induced Structural Changes of Arsenic Trioxide, an Inorganic Compound, and Organic Arsenic Derivative S-Dimethylarsino-Glutathione (SGLU; ZIO-101) in NB4 Acute Promyelocytic Leukemia (APL) Cells." Blood 106, no. 11 (2005): 4446. http://dx.doi.org/10.1182/blood.v106.11.4446.4446.
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Abstract Arsenic trioxide (As2O3; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with arsenic exposure. We studied effects of 2 arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic arsenic derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these arsenic derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.
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Kim, Eun Sun, Hoon Jai Chun, Yoon Tae Jeen, et al. "Novel probe-based quantative image of mitochondria in live colon cancer tissues by multiphoton microscopy." Journal of Clinical Oncology 34, no. 4_suppl (2016): 581. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.581.
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581 Background: Multiphoton endomicroscopy is the recentely updated technique for endoscopy and virtual image and optical sectioning. However optimized probe has not been established for multiphoton endomicroscopic image. Therefore we developed novel probe for mitochondria and applied for colon neoplasm tissues. In cancer cell, abnormally increased mitochondrial replication is related mitochondrial dysfunction and Warburg effect. Methods: We used newly developed multiphoton probe for micochondria imaging which are made using benzofuran derivative (BFP, maximal multiphoton fluorescence at 570 nm). Fresh mucosal tissues of colonic adenoma and adenocarcinoma were obtained from endoscopic biopsy. Multiphoton probe BFP for mitochondria was stained for tissues and imaging performed using multiphoton microscopy. Results: BFP shows high enhancement factor upon binding mitochondria, good selectivity, cell permeability, and can readily detect mitochondria in human tissues by multiphoton microscopy. Mitochondria were detected in human colon mucosa tissues. Calculated mitochondria area were increased in adenocarcinoma tissues compared to normal mucosal tissues. Conclusions: Newly developed multiphoton probe for mitochondria are usable to image human live colon tissues.
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Wyss, M., T. Wallimann, and J. Köhrle. "Selective labelling and inactivation of creatine kinase isoenzymes by the thyroid hormone derivative N-bromoacetyl-3,3′,5-tri-iodo-l-thyronine." Biochemical Journal 291, no. 2 (1993): 463–72. http://dx.doi.org/10.1042/bj2910463.
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Besides their well-known regulation of transcription by binding to nuclear receptors, thyroid hormones have been suggested to have direct effects on mitochondria. In a previous study, incubation of rat heart mitochondria with 125I-labelled N-bromoacetyl-3,3′,5-tri-iodo-L-thyronine (BrAcT3), a thyroid hormone derivative with an alkylating side chain, resulted in the selective labelling of a protein doublet around M(r) 45,000 on SDS/polyacrylamide gels [Rasmussen, Köhrle, Rokos and Hesch (1989) FEBS Lett. 255, 385-390]. Now, this protein doublet has been identified as mitochondrial creatine kinase (Mi-CK). Immunoblotting experiments with the cytoplasmic and mitochondrial fractions of rat heart, brain and liver, as well as inactivation studies with the purified chicken CK isoenzymes have further demonstrated that all four CK isoenzymes (Mia-, Mib-, M- and B-CK) are indeed selectively labelled by BrAcT3. However, in contrast with their bromoalkyl derivatives, thyroid hormones themselves did not compete for CK labelling, suggesting that not the thyroid hormone moiety but rather the bromoacetyl-driven alkylation of the highly reactive ‘essential’ thiol group of CK accounts for this selective labelling. Therefore the assumption that CK isoenzymes are thyroid-hormone-binding proteins has to be dismissed. Instead, bromoacetyl-based reagents may allow a very specific covalent modification and inactivation of CK isoenzymes in vitro and in vivo.
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Liu, Bing, Jiangbo Jin, Ziyu Zhang, Li Zuo, Meixiu Jiang та Caifeng Xie. "Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2–AMPK–PGC1α signaling pathway". Biochemistry and Cell Biology 97, № 4 (2019): 397–405. http://dx.doi.org/10.1139/bcb-2018-0310.
Full textAbstract:
Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2–AMPK–PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.
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Panov, Alexander, Zulfiya Orynbayeva, Valentin Vavilin, and Vyacheslav Lyakhovich. "Fatty Acids in Energy Metabolism of the Central Nervous System." BioMed Research International 2014 (2014): 1–22. http://dx.doi.org/10.1155/2014/472459.
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In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain’s energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcileβ-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.
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Epstein, Charles B., James A. Waddle, Walker Hale, et al. "Genome-wide Responses to Mitochondrial Dysfunction." Molecular Biology of the Cell 12, no. 2 (2001): 297–308. http://dx.doi.org/10.1091/mbc.12.2.297.
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Mitochondrial dysfunction can lead to diverse cellular and organismal responses. We used DNA microarrays to characterize the transcriptional responses to different mitochondrial perturbations inSaccharomyces cerevisiae. We examined respiratory-deficient petite cells and respiratory-competent wild-type cells treated with the inhibitors of oxidative phosphorylation antimycin, carbonyl cyanide m-chlorophenylhydrazone, or oligomycin. We show that respiratory deficiency, but not inhibition of mitochondrial ATP synthesis per se, induces a suite of genes associated with both peroxisomal activities and metabolite-restoration (anaplerotic) pathways that would mitigate the loss of a complete tricarboxylic acid cycle. The array data suggested, and direct microscopic observation of cells expressing a derivative of green fluorescent protein with a peroxisomal matrix-targeting signal confirmed, that respiratory deficiency dramatically induces peroxisome biogenesis. Transcript profiling of cells harboring null alleles ofRTG1, RTG2, or RTG3, genes known to control signaling from mitochondria to the nucleus, suggests that there are multiple pathways of cross-talk between these organelles in yeast.
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Ozcan, Cevher, Martin Bienengraeber, Petras P. Dzeja, and Andre Terzic. "Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 2 (2002): H531—H539. http://dx.doi.org/10.1152/ajpheart.00552.2001.
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K+ channel openers have been recently recognized for their ability to protect mitochondria from anoxic injury. Yet the mechanism responsible for mitochondrial preservation under oxidative stress is not fully understood. Here, mitochondria were isolated from rat hearts and subjected to 20-min anoxia, followed by reoxygenation. At reoxygenation, increased generation of reactive oxygen species (ROS) was associated with reduced ADP-stimulated oxygen consumption, blunted ATP production, and disrupted mitochondrial structural integrity coupled with cytochrome c release. The prototype K+ channel opener diazoxide markedly reduced mitochondrial ROS production at reoxygenation with a half-maximal effect of 29 μM. Diazoxide also preserved oxidative phosphorylation and mitochondrial membrane integrity, as indicated by electron microscopy and reduced cytochrome c release. The protective effect of diazoxide was reproduced by the structurally distinct K+ channel opener nicorandil and antagonized by 5-hydroxydecanoic acid, a short-chain fatty acid derivative and presumed blocker of mitochondrial ATP-sensitive K+ channels. Opener-mediated mitochondrial protection was simulated by the free radical scavenger system composed of superoxide dismutase and catalase. However, the effect of openers on ROS production was maintained in nominally K+-free medium in the presence or absence of the K+ ionophore valinomycin and was mimicked by malonate, a modulator of the mitochondrial redox state. This suggests the existence of a K+ conductance-independent pathway for mitochondrial protection targeted by K+ channel openers. Thus the cardioprotecive mechanism of K+ channel openers includes direct attenuation of mitochondrial oxidant stress at reoxygenation.
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Dremza, I. K., V. T. Cheshchevik, S. V. Zabrodskaya, et al. "Hepatotoxic efects of acetaminophen. Protective properties of tryptophan-derivatives." Biomeditsinskaya Khimiya 56, no. 6 (2010): 710–18. http://dx.doi.org/10.18097/pbmc20105606710.
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Rat intoxication with acetaminophen (APAP) (500-1500 mg/kg body weight intragastrically) caused a considerable dose-dependent decrease in reduced glutathione (GSH) level in both liver cellular cytoplasm and mitochondria (at the dose 1500 mg/kg body weight by 60% and 33%, respectively). The cytoplasmic GSH level decreased more pronounced by comparison with that in mitochondria. At the same time, we did not observe any inactivation of the mitochondrial enzymes: succinate dehydrogenase, α-ketoglutarate dehydrogenase, glutathione peroxidase despite of mitochondrial GSH consumption; also we did not observe any decrease in the respiratory activity of liver mitochondria isolated from APAP-intoxicated rats. A tryptophan derivative, melatonin (10 mg/kg body weight), did not prevent intramitochondrial GSH oxidation, but decreased the hepatoxity of APAP, diminishing the activities of AlT and AsT as well as bilirubin level in blood plasma of intoxicated rats. N-acetyl-nitrosotryptophan (a nitric oxide donor) did not exhibit any hepatoprotective effects.
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Lin, Chuchu, Xuan Yang, Huatian Li, et al. "Self-assembled nanomedicine combining a berberine derivative and doxorubicin for enhanced antitumor and antimetastatic efficacy via mitochondrial pathways." Nanoscale 13, no. 13 (2021): 6605–23. http://dx.doi.org/10.1039/d1nr00032b.
Full textAbstract:
A self-assembled nanomedicine combining Ber and Dox with high drug loading was developed, which could translocate Dox from the nucleus to mitochondria and finally inhibit tumor proliferation and metastasis simultaneously via mitochondrial pathways.
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Vestweber, D., and G. Schatz. "Mitochondria can import artificial precursor proteins containing a branched polypeptide chain or a carboxy-terminal stilbene disulfonate." Journal of Cell Biology 107, no. 6 (1988): 2045–49. http://dx.doi.org/10.1083/jcb.107.6.2045.
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A purified, artificial precursor protein was used as a transport vehicle to test the tolerance of the mitochondrial protein import system. The precursor was a fusion protein consisting of mouse dihydrofolate reductase linked to a yeast mitochondrial presequence; it contained a unique cysteine as its COOH-terminal residue. This COOH-terminal cysteine was covalently coupled to either a stilbene disulfonate derivative or, with the aid of a bifunctional cross-linker, to one of the free amino groups of horse heart cytochrome c. Coupling to horse heart cytochrome c generated a mixture of branched polypeptide chains since this cytochrome lacks a free alpha-amino group. Both adducts were imported and cleaved by isolated yeast mitochondria. The mitochondrial protein import machinery can thus transport more complex structures and even highly charged "membrane-impermeant" organic molecules. This suggests that transport occurs through a hydrophilic environment.
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Belosludtseva, Natalia V., Vlada S. Starinets, Lyubov L. Pavlik, Irina B. Mikheeva, Mikhail V. Dubinin, and Konstantin N. Belosludtsev. "The Effect of S-15176 Difumarate Salt on Ultrastructure and Functions of Liver Mitochondria of C57BL/6 Mice with Streptozotocin/High-Fat Diet-Induced Type 2 Diabetes." Biology 9, no. 10 (2020): 309. http://dx.doi.org/10.3390/biology9100309.
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S-15176, a potent derivative of the anti-ischemic agent trimetazidine, was reported to have multiple effects on the metabolism of mitochondria. In the present work, the effect of S-15176 (1.5 mg/kg/day i.p.) on the ultrastructure and functions of liver mitochondria of C57BL/6 mice with type 2 diabetes mellitus (T2DM) induced by a high-fat diet combined with a low-dose streptozotocin injection was examined. An electron microscopy study showed that T2DM induced mitochondrial swelling and a reduction in the number of liver mitochondria. The number of mtDNA copies in the liver in T2DM decreased. The expression of Drp1 slightly increased, and that of Mfn2 and Opa1 somewhat decreased. The treatment of diabetic animals with S-15176 prevented the mitochondrial swelling, normalized the average mitochondrial size, and significantly decreased the content of the key marker of lipid peroxidation malondialdehyde in liver mitochondria. In S-15176-treated T2DM mice, a two-fold increase in the expression of the PGC-1α and a slight decrease in Drp 1 expression in the liver were observed. The respiratory control ratio, the level of mtDNA, and the number of liver mitochondria of S-15176-treated diabetic mice tended to restore. S-15176 did not affect the decrease in expression of Parkin and Opa1 in the liver of diabetic animals, but slightly suppressed the expression of these proteins in the control. The modulatory effect of S-15176 on dysfunction of liver mitochondria in T2DM can be related to the stimulation of mitochondrial biogenesis and the inhibition of lipid peroxidation in the organelles.
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Raitz, Ismael, Roberto Y. de Souza Filho, Lorena P. de Andrade, Jose R. Correa, Brenno A. D. Neto, and Ronaldo A. Pilli. "Preferential Mitochondrial Localization of a Goniothalamin Fluorescent Derivative." ACS Omega 2, no. 7 (2017): 3774–84. http://dx.doi.org/10.1021/acsomega.7b00416.
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Mao, Gaowei, George A. Kraus, Ikyon Kim, Michael E. Spurlock, Theodore B. Bailey, and Donald C. Beitz. "Effect of a mitochondria-targeted vitamin E derivative on mitochondrial alteration and systemic oxidative stress in mice." British Journal of Nutrition 106, no. 1 (2011): 87–95. http://dx.doi.org/10.1017/s0007114510005830.
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The objective of the present study was to determine whether a mitochondria-targeted vitamin E derivative (MitoVit E) would affect certain mitochondrial parameters, as well as systemic oxidative stress. A total of sixty-four mice were fed a high-fat (HF) diet for 5 weeks. They were then switched to either a low-fat (LF) or a medium-fat (MF) diet, and administered orally with MitoVit E (40 mg MitoVit E/kg body weight) or drug vehicle (10 % (v/v) ethanol in 0·9 % (w/v) NaCl solution), every other day for 5 weeks. Mitochondrial ATP and H2O2 production rates in both the liver and the gastrocnemius were not affected by MitoVit E administration in either LF or MF diet-fed mice. However, the number and average size of the subsarcolemmal mitochondria, but not the intermyofibrillar mitochondria, from the soleus muscle were significantly higher in the MF group receiving MitoVit E (MF-E) than in the MF group receiving vehicle only (MF-C). After the mice were switched from the HF diet to the four dietary treatments (LF-C, LF-E, MF-C and MF-E), the decrease in urinary isoprostane concentration was significantly greater in the LF-E group than in the other three groups during the whole study (weeks 6–10). In addition, MitoVit E significantly increased plasma superoxide dismutase (SOD) activity in the MF diet-fed group without affecting plasma glutathione peroxidase activity or H2O2 levels. Overall, these data suggest that MitoVit E affects subsarcolemmal mitochondrial density and systemic oxidative stress parameters such as plasma SOD activity and urinary isoprostane concentration.
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Baburina, Yulia, Irina Odinokova, and Olga Krestinina. "Carbenoxolon Is Capable to Regulate the Mitochondrial Permeability Transition Pore Opening in Chronic Alcohol Intoxication." International Journal of Molecular Sciences 22, no. 19 (2021): 10249. http://dx.doi.org/10.3390/ijms221910249.
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Background: carbenoxolone, which is a derivative of glyceretic acid, is actively used in pharmacology for the treatment of diseases of various etiologies. In addition, we have shown carbenoxolone as an effective inducer of mitochondrial permeability transition pore in rat brain and liver mitochondria. Methods: in the course of this work, comparative studies were carried out on the effect of carbenoxolone on the parameters of mPTP functioning in mitochondria isolated from the liver of control and alcoholic rats. Results: within the framework of this work, it was found that carbenoxolone significantly increased its effect in the liver mitochondria of rats with chronic intoxication. In particular, this was expressed in a reduction in the lag phase, a decrease in the threshold calcium concentration required to open a pore, an acceleration of high-amplitude cyclosporin-sensitive swelling of mitochondria, as well as an increase in the effect of carbenoxolone on the level of mitochondrial membrane-bound proteins. Thus, as a result of the studies carried out, it was shown that carbenoxolone is involved in the development/modulation of alcohol tolerance and dependence in rats.
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Chagoya de Sánchez, Victoria, Lidia Martínez-Pérez, Rolando Hernández-Muñoz, and Gabriela Velasco-Loyden. "Recovery of the Cell Cycle Inhibition inCCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305." International Journal of Hepatology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/212530.
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Introduction. Cirrhosis is a chronic degenerative illness characterized by changes in normal liver architecture, failure of hepatic function, and impairment of proliferative activity. The aim of this study is to know how IFC-305 compound induces proliferation of the liver during reversion of cirrhosis.Methods. Once cirrhosis has been installed by CCl4treatment for 10 weeks in male Wistar rats, they were divided into four groups: two received saline and two received the compound; all were euthanized at 5 and 10 weeks of treatment. Liver homogenate, mitochondria, and nucleus were used to measure cyclins, CDKs, and cell cycle regulatory proteins PCNA, pRb, p53, E2F, p21, p27, HGF, liver ATP, and mitochondrial function.Results. Diminution and small changes were observed in the studied proteins in the cirrhotic animals without treatment. The IFC-305-treated rats showed a clear increase in most of the proteins studied mainly in PCNA and CDK6, and a marked increased in ATP and mitochondrial function.Discussion/Conclusion. IFC-305 induces a recovery of the cell cycle inhibition promoting recovery of DNA damage through the action of PCNA and p53. The increase in energy and preservation of mitochondrial function contribute to recovering the proliferative function.
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Kubálková, Janka, Vladimíra Tomečková, Pál Perjési, and Juraj Guzy. "Assessment of the effect of cyclic chalcone analogues on mitochondrial membrane and DNA." Open Life Sciences 4, no. 1 (2009): 90–96. http://dx.doi.org/10.2478/s11535-008-0057-y.
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AbstractThe cytotoxic and protective effects of selected synthetic chalcone analogues have been shown in previous studies. We studied their cytotoxic effect on the modification of mitochondrial membrane potential and on DNA. The first spectral information about the methoxy group as well as the dimethylamino substituent in E-2-arylmethylene-1-benzosuberones molecule was obtained by absorption and emission spectra. The cytotoxic effect of both cyclic chalcone analogues on DNA were detected by alkaline single-cell gel electrophoresis. Better fluorescent chalcone analogue E-2-(4′-dimethylamino-benzylidene)-1-benzosuberone was studied further in fresh isolated mitochondria. The decrease of rat liver mitochondria membrane potential (Δψ) was observed by fluorescence emission spectra. For the collapsing of mitochondrial potentials and as the negative control of mitochondrial function the CCCP uncoupler was used. The absorption maximum of the methoxy group was found at a shorter wavelength (λ = 335 nm) than that of the dimethylamino group (λ = 406 nm). The excitation spectra were very similar to the absorption spectra for both molecules but the emission spectra showed a better fluorescence for dimethylamino derivative. After the addition of E-2-(4′-dimethylamino-benzylidene)-1-benzosuberone to the intact mitochondria the decrease of mitochondrial membrane potential Δψ was observed by emisssion fluorescence spectra. Both cyclic chalcone analogues induced DNA damage, which was detected by alkaline comet assay. Mainly the apoptotic cells were detected, but necrotic cells were also present. Similarities in the percentages of DNA migration from the head were observed in both treatment groups. Both benzosuberones, with dimethylamino- and methoxy- substituent, were very active biologically, as shown by DNA results of the comet assay. Due to its better fluorescence properties, only the fluorophore with dimethylamino substituent was selected for further study of the function of rat liver mitochondria. Decline of mitochondrial function as well as mitochondrial DNA damage were evident between experimental and control groups.
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Muto, Yoshinori, Yumiko Tanabe, Kiyoshi Kawai, Yukio Okano, and Hideo Iio. "Climacostol inhibits Tetrahymena motility and mitochondrial respiration." Open Life Sciences 6, no. 1 (2011): 99–104. http://dx.doi.org/10.2478/s11535-010-0100-7.
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AbstractClimacostol is a resorcinol derivative that is produced by the ciliate Climacostomum virens. Exposure to purified climacostol results in lethal damage to the predatory ciliate Dileptus margaritifer and several other ciliates. To elucidate the mechanism of climacostol toxic action, we have investigated the effects of this compound on the swimming behavior of Tetrahymena thermophila and the respiratory system of isolated rat liver mitochondria. When added to living T. thermophila cells, climacostol markedly increased the turning frequency that was accompanied by a decrease in swimming velocity and subsequently by cell death. Observations by DIC and fluorescence microscopy showed morphological alterations in climacostol treated T. thermophila, indicating that climacostol might exert cytotoxic action on this organism. In the experiment with isolated rat liver mitochondria, climacostol was found to inhibit the NAD-linked respiration, but had no apparent effect on succinate-linked respiration. This finding indicates that climacostol specifically inhibits respiratory chain complex I in mitochondria. The combination of results suggest that the inhibition of mitochondrial respiration may be the cytotoxic mechanism of climacostol’s defenses against predatory protozoa.
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Yoshihisa, Tohru, Kaori Yunoki-Esaki, Chie Ohshima, Nobuyuki Tanaka, and Toshiya Endo. "Possibility of Cytoplasmic pre-tRNA Splicing: the Yeast tRNA Splicing Endonuclease Mainly Localizes on the Mitochondria." Molecular Biology of the Cell 14, no. 8 (2003): 3266–79. http://dx.doi.org/10.1091/mbc.e02-11-0757.
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Pre-tRNA splicing has been believed to occur in the nucleus. In yeast, the tRNA splicing endonuclease that cleaves the exon-intron junctions of pre-tRNAs consists of Sen54p, Sen2p, Sen34p, and Sen15p and was thought to be an integral membrane protein of the inner nuclear envelope. Here we show that the majority of Sen2p, Sen54p, and the endonuclease activity are not localized in the nucleus, but on the mitochondrial surface. The endonuclease is peripherally associated with the cytosolic surface of the outer mitochondrial membrane. A Sen54p derivative artificially fixed on the mitochondria as an integral membrane protein can functionally replace the authentic Sen54p, whereas mutant proteins defective in mitochondrial localization are not fully active. sen2 mutant cells accumulate unspliced pre-tRNAs in the cytosol under the restrictive conditions, and this export of the pre-tRNAs partly depends on Los1p, yeast exportin-t. It is difficult to explain these results from the view of tRNA splicing in the nucleus. We rather propose a new possibility that tRNA splicing occurs on the mitochondrial surface in yeast.
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SMITH, Vernon R., Ian M. FEARNLEY, and John E. WALKER. "Altered chromatographic behaviour of mitochondrial ADP/ATP translocase induced by stabilization of the protein by binding of 6′-O-fluorescein-atractyloside." Biochemical Journal 376, no. 3 (2003): 757–63. http://dx.doi.org/10.1042/bj20030942.
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Atractyloside (ATR) is a high-affinity specific inhibitor of the mitochondrial ADP/ATP translocase (AAT). The binding of a fluorescent derivative, 6´-O-fluorescein-ATR (FATR), to mitochondria has been characterized. The binding constants obtained are in agreement with previously published values for ATR, demonstrating that FATR is a suitable probe of the AAT. AAT inhibited by FATR (FATR-AAT) was solubilized in dodecyl maltoside and purified by two separate ion-exchange chromatography steps at different pHs, which allowed FATR-AAT to be purified to homogeneity. The presence of the bound fluorescent probe enabled the inhibited AAT to be distinguished from the unliganded protein during chromatography, as they were markedly different in their chromatographic behaviour. The purified FATR-AAT was dimeric and in a single major conformation containing 1 mole FATR per mole of AAT dimer. In contrast, uninhibited AAT was monomeric and conformationally unstable. Use of the fluorescent ATR derivative in the development of the protocol enabled the stable dimeric AAT to be monitored directly and purified more effectively. The purification protocol was repeated using non-derivatized ATR, and highly pure AAT was obtained that was devoid of other members of the mitochondrial carrier family.
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Li, DengFeng, James A. Snipes, Mariana Murea, et al. "An Acidic Environment Induces APOL1-Associated Mitochondrial Fragmentation." American Journal of Nephrology 51, no. 9 (2020): 695–704. http://dx.doi.org/10.1159/000509989.
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Background: Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction. Methods: Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction. Results: After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction. Conclusion: Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy.
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Orlicka-Płocka, Marta, Dorota Gurda-Wozna, Agnieszka Fedoruk-Wyszomirska, and Eliza Wyszko. "Circumventing the Crabtree effect: forcing oxidative phosphorylation (OXPHOS) via galactose medium increases sensitivity of HepG2 cells to the purine derivative kinetin riboside." Apoptosis 25, no. 11-12 (2020): 835–52. http://dx.doi.org/10.1007/s10495-020-01637-x.
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AbstractSmall-molecule compound-based therapies have provided new insights into cancer treatment against mitochondrial impairment. N6-furfuryladenosine (kinetin riboside, KR) is a purine derivative and an anticancer agent that selectively affects the molecular pathways crucial for cell growth and apoptosis by interfering with mitochondrial functions and thus might be a potential mitotoxicant. Metabolism of cancer cells is predominantly based on the Crabtree effect that relies on glucose-induced inhibition of cell respiration and thus on oxidative phosphorylation (OXPHOS), which supports the survival of cancer cells in metabolic stress conditions. The simplest way to circumvent this phenomenon is to replace glucose with galactose in the culture environment. Consequently, cells become more sensitive to mitochondrial perturbations caused by mitotoxicants. In the present study, we evaluated several cellular parameters and investigated the effect of KR on mitochondrial functions in HepG2 cells forced to rely mainly on OXPHOS. We showed that KR in the galactose environment is a more potent apoptosis-inducing agent. KR decreases the mitochondrial membrane potential, reduces glutathione level, depletes cellular ATP, and induces reactive oxygen species (ROS) production in the OXPHOS state, leading to the loss of cell viability. Taken together, these results demonstrate that KR directly acts on the mitochondria to limit their function and that the sensitivity of cells is dependent on their ability to cope with energetic stress.
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Raimondi, Michela, Fabrizio Fontana, Monica Marzagalli та ін. "Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells". Apoptosis 26, № 5-6 (2021): 277–92. http://dx.doi.org/10.1007/s10495-021-01668-y.
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Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.
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Mehta, Nihar, Praneet Marwah, and David Njus. "Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?" Cells 8, no. 1 (2019): 59. http://dx.doi.org/10.3390/cells8010059.
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Parkinson’s disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron’s autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson’s disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson’s disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson’s disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson’s disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.
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PETROVA, Ventsislava Y., Diane DRESCHER, Anna V. KUJUMDZIEVA, and Manfred J. SCHMITT. "Dual targeting of yeast catalase A to peroxisomes and mitochondria." Biochemical Journal 380, no. 2 (2004): 393–400. http://dx.doi.org/10.1042/bj20040042.
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Yeast catalase A (Cta1p) contains two peroxisomal targeting signals (SSNSKF) localized at its C-terminus and within the N-terminal third of the protein, which both can target foreign proteins to peroxisomes. In the present study we demonstrated that Cta1p can also enter mitochondria, although the enzyme lacks a classical mitochondrial import sequence. Cta1p co-targeting was studied in a catalase A null mutant after growth on different carbon sources, and expression of a Cta1p–GFP (green fluorescent protein)-fusion protein or a Cta1p derivative containing either a c-Myc epitope (Cta1pmyc) or a SKF-extended tag (Cta1pmyc-SKF). Peroxisomal and mitochondrial co-import of catalase A were tested qualitatively by fluorescence microscopy and functional complementation of a Δcta1 null mutation, and quantitatively by subcellular fractionation followed by Western blot analysis and enzyme activity assays. Efficient Cta1p import into peroxisomes was observed when cells were cultivated under peroxisome-inducing conditions (i.e. growth on oleate), whereas significant co-import of Cta1p–GFP into mitochondria occurred when cells were grown under respiratory conditions that favour oxygen stress and ROS (reactive oxygen species) accumulation within this organelle. In particular, when cells were grown on the non-fermentable carbon source raffinose, respiration is maximally enhanced, and catalase A was efficiently targeted to the mitochondrial matrix where it presumably functions as scavenger of H2O2 and mitochondrial-derived ROS.
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Wang, Hui, Xiaohe Tian, Lijuan Guan, et al. "Targeting mitochondrial DNA with a two-photon active Ru(ii) phenanthroline derivative." Journal of Materials Chemistry B 4, no. 17 (2016): 2895–902. http://dx.doi.org/10.1039/c6tb00433d.
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Zhao, Mei-Xia, Er-Zao Zeng, Yang Li, and Chao-Jie Wang. "A study on effects of naphthalimide derivative-capped quantum dots on the cellular internalization, proliferation, and apoptosis ability." J. Mater. Chem. B 2, no. 42 (2014): 7351–59. http://dx.doi.org/10.1039/c4tb01048e.
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Belosludtseva, Natalia V., Vlada S. Starinets, Irina B. Mikheeva, et al. "Effect of the MPT Pore Inhibitor Alisporivir on the Development of Mitochondrial Dysfunction in the Heart Tissue of Diabetic Mice." Biology 10, no. 9 (2021): 839. http://dx.doi.org/10.3390/biology10090839.
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Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with the mitochondrial permeability transition (MPT) pore opening being considered as one of its possible mechanisms. The effect of alisporivir, a non-immunosuppressive cyclosporin derivative and a selective inhibitor of the MPT pore opening, on the ultrastructure and functions of the heart mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections was studied. The treatment of diabetic animals with alisporivir (2.5 mg/kg ip for 20 days) increased the rate of glucose clearance during the glucose tolerance test. The blood glucose level and the indicator of heart rate in alisporivir-treated diabetic mice tended to restore. An electron microscopy analysis showed that alisporivir prevented mitochondrial swelling and ultrastructural alterations in cardiomyocytes of diabetic mice. Alisporivir canceled the diabetes-induced increases in the susceptibility of heart mitochondria to the MPT pore opening and the level of lipid peroxidation products, but it did not affect the decline in mitochondrial oxidative phosphorylation capacity. The mRNA expression levels of Pink1 and Parkin in the heart tissue of alisporivir-treated diabetic mice were elevated, suggesting the stimulation of mitophagy. In parallel, alisporivir decreased the level of mtDNA in the heart tissue. These findings suggest that targeting the MPT pore opening by alisporivir alleviates the development of mitochondrial dysfunction in the diabetic heart. The cardioprotective effect of the drug in diabetes can be mediated by the induction of mitophagy and the inhibition of lipid peroxidation in the organelles.
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Andreidesz, Kitti, Aliz Szabo, Dominika Kovacs, et al. "Cytostatic Effect of a Novel Mitochondria-Targeted Pyrroline Nitroxide in Human Breast Cancer Lines." International Journal of Molecular Sciences 22, no. 16 (2021): 9016. http://dx.doi.org/10.3390/ijms22169016.
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Mitochondria have emerged as a prospective target to overcome drug resistance that limits triple-negative breast cancer therapy. A novel mitochondria-targeted compound, HO-5114, demonstrated higher cytotoxicity against human breast cancer lines than its component-derivative, Mito-CP. In this study, we examined HO-5114′s anti-neoplastic properties and its effects on mitochondrial functions in MCF7 and MDA-MB-231 human breast cancer cell lines. At a 10 µM concentration and within 24 h, the drug markedly reduced viability and elevated apoptosis in both cell lines. After seven days of exposure, even at a 75 nM concentration, HO-5114 significantly reduced invasive growth and colony formation. A 4 h treatment with 2.5 µM HO-5114 caused a massive loss of mitochondrial membrane potential, a decrease in basal and maximal respiration, and mitochondrial and glycolytic ATP production. However, reactive oxygen species production was only moderately elevated by HO-5114, indicating that oxidative stress did not significantly contribute to the drug’s anti-neoplastic effect. These data indicate that HO-5114 may have potential for use in the therapy of triple-negative breast cancer; however, the in vivo toxicity and anti-neoplastic effectiveness of the drug must be determined to confirm its potential.