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International Journal of Molecular... Jan 2024Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones, a new class of antitumor agents. Our study of the mechanism of...
Recent works identified ClpXP, mitochondrial caseinolytic protease, as the only target of imipridones, a new class of antitumor agents. Our study of the mechanism of imipridone derivative TR-57 action in SUM159 human breast cancer cells demonstrated mitochondrial fragmentation, degradation of mitochondrial mtDNA and mitochondrial dysfunction due to inhibition of Complex I and Complex II activity. Complete inhibition of oxidative phosphorylation accompanied 90, 94, 88 and 87% decreases in the content of Complex I, II, III and IV proteins, respectively. The content of the FF-ATPase subunits decreased sharply by approximately 35% after 24 h and remained unchanged up to 72 h of incubation with TR-57. At the same time, a disappearance of the ATPIF1, the natural inhibitor of mitochondrial FF-ATPase, was observed after 24 h exposure to TR-57. ATPase inhibitor oligomycin did not affect the mitochondrial membrane potential in intact SUM159, whereas it caused a 65% decrease in TR-57-treated cells. SUM159 cells incubated with TR57 up to 72 h retained the level of proteins facilitating the ATP transfer across the mitochondrial membranes: VDAC1 expression was not affected, while expression of ANT-1/2 and APC2 increased by 20% and 40%, respectively. Thus, our results suggest that although TR-57 treatment leads to complete inhibition of respiratory chain activity of SUM159 cells, hydrolysis of cytoplasmic ATP by reversal activity of FF-ATPase supports mitochondrial polarization.
Topics: Humans; Mitochondria; Membrane Potential, Mitochondrial; Adenosine Triphosphatases; Adenine Nucleotide Translocator 2; Electron Transport Complex I; Mitochondrial Diseases; Adenosine Triphosphate
PubMed: 38256264
DOI: 10.3390/ijms25021193 -
Anti-cancer Drugs Apr 2024The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly...
The development of chemo-resistance in nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge, and its underlying mechanisms remain poorly understood. In our previous studies, we highlighted the association between isoprenylcysteine carboxylmethyltransferase (ICMT) and chemoresistance in NPC. In this current research, we revealed that both 5-FU and cisplatin-resistant NPC cells exhibited elevated mitochondrial function and increased expression of mitochondrial genes, independent of ICMT. Our investigations further showed that classic mitochondrial inhibitors, such as oligomycin, antimycin, and rotenone, were notably more effective in reducing viability in chemo-resistant NPC cells compared to parental cells. Moreover, we identified two antimicrobial drugs, tigecycline and atovaquone, recognized as mitochondrial inhibitors, as potent agents for decreasing chemo-resistant NPC cells by targeting mitochondrial respiration. Remarkably, tigecycline and atovaquone, administered at tolerable doses, inhibited chemo-resistant NPC growth in mouse models and extended overall survival rates. This work unveils the efficacy of mitochondrial inhibition as a promising strategy to overcome chemo-resistance in NPC. Additionally, our findings highlight the potential repurposing of clinically available drugs like tigecycline and atovaquone for treating NPC patients who develop chemoresistance.
Topics: Animals; Mice; Humans; Nasopharyngeal Carcinoma; Drug Resistance, Neoplasm; Atovaquone; Tigecycline; Cell Line, Tumor; Cisplatin; Mitochondria; Nasopharyngeal Neoplasms
PubMed: 38215016
DOI: 10.1097/CAD.0000000000001566 -
The Journal of Antibiotics Mar 2024Peptidoglycan is an important macromolecule in bacterial cell walls to maintain cell integrity, and its biosynthetic pathway has been well studied. Recently, we...
Peptidoglycan is an important macromolecule in bacterial cell walls to maintain cell integrity, and its biosynthetic pathway has been well studied. Recently, we demonstrated that some bacteria such as Xanthomonas oryzae, a pathogen causing bacterial blight of rice, used an alternative pathway for peptidoglycan biosynthesis. In this pathway, MurD2, a MurD homolog, catalyzed the attachment of L-Glu to UDP-MurNAc-L-Ala and MurL, which did not show homology to any known protein, catalyzed epimerization of the terminal L-Glu of the MurD2 product to generate UDP-MurNAc-L-Ala-D-Glu. Because the alternative pathway also operates in some other plant pathogens and opportunistic pathogens, specific inhibitors of the alternative pathway could function as pesticides and antibiotics for these pathogens. In this study, we searched for specific inhibitors of the alternative pathway from metabolites produced by actinomycetes and identified a new oligomycin-class polyketide, which was revealed to inhibit the MurD2 reaction, in culture broth of Micromonospora sp. K18-0097.
Topics: Peptidoglycan; Oligomycins; Biosynthetic Pathways; Anti-Bacterial Agents; Bacteria; Cell Wall
PubMed: 38200161
DOI: 10.1038/s41429-023-00693-0 -
Journal of Agricultural and Food... Jan 2024Oligomycins are potent antifungal and antitumor agents. Mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based metabolomic fingerprinting analysis of...
Oligomycins are potent antifungal and antitumor agents. Mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based metabolomic fingerprinting analysis of marine-derived actinomycetes in our in-house library provided an oligomycin-producing strain, sp. FXY-T5. Chemical investigation led to the discovery of five new oligomycins, 24-lumooligomycin B (), 4-lumooligomycin B (), 6-lumooligomycin B (), 40-homooligomycin B (), and 15-hydroxy-oligomycin B (), together with seven biosynthetically related known derivatives. Their structures were assigned by MS, NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. The biosynthesis pathway of oligomycins was first proposed based on the analysis of a type I modular polyketide synthase (PKS) system and targeted gene disruption. As expected, the isolated oligomycins showed significant antiagricultural fungal pathogen activity and antiproliferative properties from which the possible structure-activity relationships were first suggested. More importantly, oligomycins induced significant G1-phase cell cycle arrest on cancer cells and significantly attenuated their Cyclin D1 and PCNA expression through a β-catenin signaling pathway.
Topics: Streptomyces; Oligomycins; Antineoplastic Agents; Structure-Activity Relationship; Antifungal Agents
PubMed: 38169320
DOI: 10.1021/acs.jafc.3c06307 -
Biochimica Et Biophysica Acta.... Feb 2024Disruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear....
Disruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear. We have used N2a mouse neuroblastoma cells and primary cultures of mouse neurons and 1-methyl-4-phenylpyridinium (MPP), a known mitochondrial complex I inhibitor and the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), known to trigger a cascade of events associated with PD neuropathological features. Simultaneously, we utilized other mitochondrial toxins, including antimycin A, oligomycin, and carbonyl cyanide chlorophenylhydrazone. MPP treatment resulted in elevated levels of total cholesterol and in a Niemann Pick type C1 (NPC1)-like phenotype characterized by accumulation of cholesterol in lysosomes. Interestingly, NPC1 mRNA levels were specifically reduced by MPP. The decrease in NPC1 levels was also seen in midbrain and striatum from MPTP-treated mice and in primary cultures of neurons treated with MPP. Together with the MPP-dependent increase in intracellular cholesterol levels in N2a cells, we observed an increase in 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and a concomitant increase in the phosphorylated levels of mammalian target of rapamycin (mTOR). NPC1 knockout delayed cell death induced by acute mitochondrial damage, suggesting that transient cholesterol accumulation in lysosomes could be a protective mechanism against MPTP/MPP insult. Interestingly, we observed a negative correlation between NPC1 protein levels and disease stage, in human PD brain samples. In summary, MPP decreases NPC1 levels, elevates lysosomal cholesterol accumulation and alters mTOR signaling, adding to the existing notion that PD may rise from alterations in mitochondrial-lysosomal communication.
Topics: Animals; Humans; Mice; Cholesterol; Mammals; Mechanistic Target of Rapamycin Complex 1; Niemann-Pick C1 Protein; Parkinson Disease; Phenotype; TOR Serine-Threonine Kinases
PubMed: 38061599
DOI: 10.1016/j.bbadis.2023.166980 -
Reproduction (Cambridge, England) Feb 2024Epigenetic programming is a crucial process during early embryo development that can have a significant impact on the results of assisted reproductive technology (ART)...
IN BRIEF
Epigenetic programming is a crucial process during early embryo development that can have a significant impact on the results of assisted reproductive technology (ART) and offspring health. Here we show evidence using a bovine in vitro experiment that embryo epigenetic programing is dependent on oocyte mitochondrial bioenergetic activity during maturation.
ABSTRACT
This study investigated if oocyte and early embryo epigenetic programming are dependent on oocyte mitochondrial ATP production. A bovine in vitro experiment was performed in which oocyte mitochondrial ATP production was reduced using 5 nmol/L oligomycin A (OM; ATP synthase inhibitor) during in vitro maturation (IVM) compared to control (CONT). OM exposure significantly reduced mitochondrial ATP production rate in MII oocytes (34.6% reduction, P = 0.018) and significantly decreased embryo cleavage rate at 48 h post insemination (7.6% reduction, P = 0.031). Compared to CONT, global DNA methylation (5mC) levels were decreased in OM-exposed MII oocytes (9.8% reduction, P = 0.019) while global histone methylation (H3K9me2) was increased (9.4% increase, P = 0.024). In zygotes, OM exposure during IVM increased 5mC (22.3% increase, P < 0.001) and histone acetylation (H3K9ac, 17.3% increase, P = 0.023) levels, while H3K9me2 levels were not affected. In morulae, 5mC levels were increased (10.3% increase, P = 0.041) after OM exposure compared to CONT, while there was no significant difference in H3K9ac and H3K9me2 levels. These epigenetic alterations were not associated with any persistent effects on embryo mitochondrial ATP production rate or mitochondrial membrane potential (assessed at the four-cell stage). Also, epigenetic regulatory genes were not differentially expressed in OM-exposed zygotes or morulae. Finally, apoptotic cell index in blastocysts was increased after OM exposure during oocyte maturation (41.1% increase, P < 0.001). We conclude that oocyte and early embryo epigenetic programming are dependent on mitochondrial ATP production during IVM.
Topics: Animals; Cattle; In Vitro Oocyte Maturation Techniques; Histones; Epigenome; Oligomycins; Oocytes; Embryonic Development; Adenosine Triphosphate
PubMed: 38038651
DOI: 10.1530/REP-23-0271 -
Life Sciences Jan 2024Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of... (Review)
Review
Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.
Topics: Humans; Adenosine Triphosphatases; Carrier Proteins; Cardiovascular Diseases; Mitochondrial Proton-Translocating ATPases; Mitochondrial Diseases; Neoplasms
PubMed: 38030056
DOI: 10.1016/j.lfs.2023.122293 -
BMC Cancer Nov 2023Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse...
Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.
Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic agent. Stress-related apoptosis was triggered via a caspase cascade including the cleavage of caspase 3 and the inactivation of poly ADP ribose polymerase 1 (PARP1). The inhibition of PARP by olaparib also increased CML death in combination with TKIs. Our findings suggest a rationale for combining TKIs with 8-Cl-Ado or olaparib for future clinical studies in CML.
Topics: Humans; Tyrosine Kinase Inhibitors; Fusion Proteins, bcr-abl; Oxidative Phosphorylation; Thapsigargin; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Enzyme Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Oligomycins; Adenosine Triphosphate; Apoptosis
PubMed: 38012567
DOI: 10.1186/s12885-023-11623-6 -
The Journal of Antibiotics Feb 2024Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection...
Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection methods. A factor that contributes to malignancy are cancer stem cell-like characteristics promoted by the tumor-stromal interaction. Given that fibroblast conditioned medium (CM) promotes sphere formation of cancer cells, a cancer stem cell-like characteristic, its inhibitor could be a new anticancer agent. By exploring microbial cultures as a source, we found new compounds, namely, adenopeptins B (1) and C (2), from Acremonium sp. ESF00140. 1 and 2 selectively and potently inhibited the sphere formation of pancreatic cancer cells cultured in the fibroblast CM compared with the control medium. Oxygen consumption rate (OCR) assays showed that 1 and 2 inhibit OCR in pancreatic cancer cells. Studies of similar compounds suggested mitochondrial complex V inhibition. Therefore, results of measuring the activity of human mitochondrial complex V revealed that 1 and 2 inhibited its activity. Oligomycin A, an inhibitor of mitochondrial complex V, as well as 1 and 2, strongly inhibited the sphere formation of pancreatic cancer cells cultured in fibroblast CM. The addition of 1 and 2 to pancreatic cancer cells cultured in fibroblast CM increased reactive oxygen species (ROS) production compared with that in the control medium. In pancreatic cancer cells cultured in fibroblast CM, mitochondria significantly influence sphere formation, and targeting their function with 1 and 2 might provide a new therapeutic approach for pancreatic cancer.
Topics: Humans; Cell Line, Tumor; Pancreatic Neoplasms; Antineoplastic Agents; Reactive Oxygen Species; Mitochondria
PubMed: 38001285
DOI: 10.1038/s41429-023-00679-y -
Journal of Medicinal Chemistry Jan 2024Finding a therapy for ischemia-reperfusion injury, which consists of cell death following restoration of blood flowing into the artery affected by ischemia, is a strong...
Finding a therapy for ischemia-reperfusion injury, which consists of cell death following restoration of blood flowing into the artery affected by ischemia, is a strong medical need. Nowadays, only the use of broad-spectrum molecular therapies has demonstrated a partial efficacy in protecting the organs following reperfusion, while randomized clinical trials focused on more specific drug targets have failed. In order to overcome this problem, we applied a combination of molecular modeling and chemical synthesis to identify novel spiropiperidine-based structures active in mitochondrial permeability transition pore opening inhibition as a key process to enhance cell survival after blood flow restoration. Our results were confirmed by biological assay on an in vitro cell model on HeLa and human renal proximal tubular epithelial cells and pave the way to further investigation on an in vivo model system.
Topics: Humans; Mitochondrial Membrane Transport Proteins; Oligomycins; Reperfusion Injury; Mitochondrial Permeability Transition Pore; Epithelial Cells
PubMed: 37991993
DOI: 10.1021/acs.jmedchem.3c01792