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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 -
British Journal of Pharmacology Mar 2022Ca influx via TRPV4 channels triggers Ca release from the IP -sensitive internal store to generate repetitive oscillations. Although mitochondria are acknowledged...
BACKGROUND AND PURPOSE
Ca influx via TRPV4 channels triggers Ca release from the IP -sensitive internal store to generate repetitive oscillations. Although mitochondria are acknowledged regulators of IP -mediated Ca release, how TRPV4-mediated Ca signals are regulated by mitochondria is unknown. We show that depolarised mitochondria switch TRPV4 signalling from relying on Ca -induced Ca release at IP receptors to being independent of Ca influx and instead mediated by ATP release via pannexins.
EXPERIMENTAL APPROACH
TRPV4-evoked Ca signals were individually examined in hundreds of cells in the endothelium of rat mesenteric resistance arteries using the indicator Cal520.
KEY RESULTS
TRPV4 activation with GSK1016790A (GSK) generated repetitive Ca oscillations that required Ca influx. However, when the mitochondrial membrane potential was depolarised, by the uncoupler CCCP or complex I inhibitor rotenone, TRPV4 activation generated large propagating, multicellular, Ca waves in the absence of external Ca . The ATP synthase inhibitor oligomycin did not potentiate TRPV4-mediated Ca signals. GSK-evoked Ca waves, when mitochondria were depolarised, were blocked by the TRPV4 channel blocker HC067047, the SERCA inhibitor cyclopiazonic acid, the PLC blocker U73122 and the inositol trisphosphate receptor blocker caffeine. The Ca waves were also inhibited by the extracellular ATP blockers suramin and apyrase and the pannexin blocker probenecid.
CONCLUSION AND IMPLICATIONS
These results highlight a previously unknown role of mitochondria in shaping TRPV4-mediated Ca signalling by facilitating ATP release. When mitochondria are depolarised, TRPV4-mediated release of ATP via pannexin channels activates plasma membrane purinergic receptors to trigger IP -evoked Ca release.
Topics: Adenosine Triphosphate; Animals; Calcium; Calcium Signaling; Mitochondria; Rats; TRPV Cation Channels
PubMed: 34605007
DOI: 10.1111/bph.15687 -
Theriogenology Oct 2023Cellular metabolism is an important feature of spermatozoa that deserves more insights to be fully understood, in particular in porcine semen physiology. The present...
Cellular metabolism is an important feature of spermatozoa that deserves more insights to be fully understood, in particular in porcine semen physiology. The present study aims to characterize the balance between glycolytic and oxidative metabolism in boar sperm cells. Agilent Seahorse technology was used to assess both oxygen consumption rate (OCR), as an oxidative metabolism index, and extracellular acidification rate (ECAR), as a glycolytic index. Different metabolic parameters were studied on freshly ejaculated sperm cells (identified as day zero sample, d0) and after one day of storage at 17 °C in Androhep extender (d1). Mitochondrial ATP production rate (MitoATP) was higher than the glycolytic ATP production rate (glycoATP) at both d0 and d1 while at d1 the amount of ATP production decreased, in particular, due to OXPHOS reduction. Conversely, glycoATP was not significantly different between d0 and d1. Interestingly, OCR profile showed no different bioenergetic parameters (i.e. ATP turnover, basal or maximal respiration, and spare respiration) between d0 and d1, thus indicating that sperm cell metabolism was reversibly decreased by preservation conditions. Other metabolic parameters showed the same trend, irrespective of the storage time: under stressed conditions (oligomycin plus FCCP), spermatozoa showed an increase in mitochondrial respiration while the metabolic potential of glycolysis did not undergo variations when compared to baseline metabolism. The rate of oxidation of fuel substrates - glucose, fatty acids, and glutamine - showed that sperm reliance on glucose oxidation to maintain baseline respiration was higher than fatty acids or glutamine. Interestingly spermatozoa demonstrated to have a low "capacity" parameter, which indicates that they cannot use only a single fuel substrate to produce energy. This feature of sperm metabolism to be unable to increase oxidation of a particular fuel to compensate for inhibition of alternative fuel pathway(s) was demonstrated by the negative value of "flexibility". Our results showed that ATP production in boar sperm cells relied on mitochondrial oxidative metabolism in freshly ejaculated cells, while, under liquid storage conditions, their oxidative metabolism decreased while the glycolysis remained constant. These results open new fields of research in the preservation techniques of boar sperm cells.
Topics: Male; Animals; Swine; Glutamine; Semen; Energy Metabolism; Spermatozoa; Glucose; Adenosine Triphosphate
PubMed: 37517301
DOI: 10.1016/j.theriogenology.2023.07.018 -
BMC Anesthesiology Sep 2023Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces...
BACKGROUND
Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces antinociception via glycolysis and mitochondria-related pathways is still unclear.
METHODS
Right hind paw inflammatory pain in mice was induced by intraplantar injection of Freund's Complete Adjuvant (FCA). Von Frey test was then used to measure the paw withdrawal threshold. The detection of glycolysis and mitochondrial pathway-related proteins and IL-8 were determined by Western blot and ELISA. The potential interaction between Dexa and fructose-1,6-bisphosphate (FBP, a PKM2 activator) was examined by simulation predictions using molecular docking.
RESULTS
Intrathecal administration of Dexa (20 µg/20 µL) had an obvious analgesic effect in FCA-treated mice, which was counteracted by the glycolysis inhibitor 2-deoxyglucose (2-DG, 5 mg/20 µL) or the mitochondria-related pathway inhibitor oligomycin complex (Oligo, 5 µg/20 µL). In the glycolysis pathway, Dexa decreased GLUT3 and had no impact on HIF-1α expression during FCA-induced inflammation. Additionally, Dexa further increased the PKM2 level, accompanied by the formation of hydrogen bonds between Dexa and the PKM2 activator fructose-1,6-bisphosphate (FBP). In the mitochondrial pathway, Dexa downregulated the expression of Mfn2 protein but not the PGC-1α and SIRT-1 levels in the spinal cord. Moreover, both 2-DG and Oligo decreased Mfn2 expression. Finally, IL-8 level was reduced by the single or combined administration of Dexa, 2-DG, and Oligo.
CONCLUSION
Dexa attenuated IL-8 expression via glycolysis and mitochondrial pathway-related proteins, thus mediating the analgesic effect during inflammatory pain.
Topics: Animals; Mice; Interleukin-8; Molecular Docking Simulation; Fructose; Glycolysis; Mitochondria; Dexamethasone; Analgesics
PubMed: 37723417
DOI: 10.1186/s12871-023-02277-9 -
Mini Reviews in Medicinal Chemistry 2016Increasing evidence highlights the role of the ATP synthase/hydrolase, also known as F1FO-complex, as key molecular and enzymatic switch between cell life and death,... (Review)
Review
Increasing evidence highlights the role of the ATP synthase/hydrolase, also known as F1FO-complex, as key molecular and enzymatic switch between cell life and death, thus increasing the enzyme attractiveness as drug target in pharmacology. Being inhibition of ATP production usually linked to antiproliferative properties, drugs targeting the enzyme complex have been mainly considered to fight pathogen parasites and cancer. In recent years, a number of natural macrolides, produced by bacterial fermentation and structurally related to the classical enzyme inhibitor oligomycin, have been shown to bind to the membrane-embedded FO sector and to inhibit the enzyme complex by an oligomycin-like mechanism, namely by interacting with the c-ring. Other than natural macrolide antibiotics, which display variegated inhibition power on different F1FO-complexes, synthetic compounds from the diarylquinoline and organotin families also target the c-ring and strongly inhibit the enzyme. Bioinformatic insights address drug design to target FO subunits. Additionally, the possible modulation of the drug inhibition power, by amino acid substitutions or post-translational modifications of c-subunits, adds further interest to the target. The present survey on compounds targeting the c-ring and bi-directionally blocking the transmembrane proton flux which drives ATP synthesis/hydrolysis, discloses new therapeutic options to fight cancer and infections sustained by therapeutically recalcitrant microorganisms. Additionally, c-ring targeting compounds may constitute new tools to eradicate undesired biofilms and to address at the molecular level the therapy of mammalian diseases linked to mitochondrial dysfunctions. In summary, studies on the only partially known molecular interactions within the c-ring of the F1FO-complex may renew hope to counteract mammalian diseases.
Topics: Animals; Drug Discovery; Enzyme Inhibitors; Humans; Macrolides; Mitochondrial Proton-Translocating ATPases; Models, Molecular; Molecular Targeted Therapy; Organotin Compounds; Protein Conformation; Quinolines
PubMed: 26864551
DOI: 10.2174/1389557516666160211120955 -
Cancer Research Jan 2020The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite...
The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-C-glucose, U-C-glutamine, and U-C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carnitine; Cell Line, Tumor; Cell Proliferation; Cell Respiration; Crizotinib; Drug Synergism; Epoxy Compounds; Fatty Acids; Gene Expression Profiling; Glioblastoma; Glycolysis; Guanidines; Humans; Lactams, Macrocyclic; Metabolomics; Mice; Mitochondria; Mitochondrial Dynamics; Oxidative Phosphorylation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proteomics; Proto-Oncogene Proteins c-met; Reactive Oxygen Species; Xenograft Model Antitumor Assays
PubMed: 31694905
DOI: 10.1158/0008-5472.CAN-19-1389 -
Molecular Cell Jan 2021In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD) is an important co-factor for enzymatic reactions, including...
In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD, mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, HO-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens HO-triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD-mediated mitochondrial-nuclear crosstalk.
Topics: ADP-Ribosylation; Animals; Antimycin A; Cell Line; Cell Line, Tumor; Cell Nucleus; Chromatin; Electron Transport; HeLa Cells; Humans; Hydrogen Peroxide; Methacrylates; Mice; Mice, Inbred C57BL; Mitochondria; Myoblasts; NAD; Oligomycins; Osteoblasts; Poly (ADP-Ribose) Polymerase-1; Rotenone; Thiazoles
PubMed: 33450210
DOI: 10.1016/j.molcel.2020.12.034 -
Cellular and Molecular Life Sciences :... Mar 2022During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load...
During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal-fetal interface.
Topics: Abortion, Spontaneous; Animals; Apoptosis; Decidua; Female; Humans; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Macrophages; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oligomycins; Oxidative Phosphorylation; Pregnancy; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Signal Transduction; Axl Receptor Tyrosine Kinase
PubMed: 35244789
DOI: 10.1007/s00018-022-04197-2 -
Frontiers in Immunology 2021Musculoskeletal stromal cells' (MSCs') metabolism impacts cell differentiation as well as immune function. During osteogenic and adipogenic differentiation, BM-MSCs show... (Review)
Review
Musculoskeletal stromal cells' (MSCs') metabolism impacts cell differentiation as well as immune function. During osteogenic and adipogenic differentiation, BM-MSCs show a preference for glycolysis during proliferation but shift to an oxidative phosphorylation (OxPhos)-dependent metabolism. The MSC immunoregulatory fate is achieved with cell polarization, and the result is sustained production of immunoregulatory molecules (including PGE2, HGF, IL1RA, IL6, IL8, IDO activity) in response to inflammatory stimuli. MSCs adapt their energetic metabolism when acquiring immunomodulatory property and shift to aerobic glycolysis. This can be achieved hypoxia, pretreatment with small molecule-metabolic mediators such as oligomycin, or AKT/mTOR pathway modulation. The immunoregulatory effect of MSC on macrophages polarization and Th17 switch is related to the glycolytic status of the MSC. Indeed, MSCs pretreated with oligomycin decreased the M1/M2 ratio, inhibited T-CD4 proliferation, and prevented Th17 switch. Mitochondrial activity also impacts MSC metabolism. In the bone marrow, MSCs are present in a quiescent, low proliferation, but they keep their multi-progenitor function. In this stage, they appear to be glycolytic with active mitochondria (MT) status. During MSC expansion, we observed a metabolic shift toward OXPhos, coupled with an increased MT activity. An increased production of ROS and dysfunctional mitochondria is associated with the metabolic shift to glycolysis. In contrast, when MSC underwent chondro or osteoblast differentiation, they showed a decreased glycolysis and inhibition of the pentose phosphate pathway (PPP). In parallel the mitochondrial enzymatic activities increased associated with oxidative phosphorylation enhancement. MSCs respond to damaged or inflamed tissue through the transfer of MT to injured and immune cells, conveying a type of signaling that contributes to the restoration of cell homeostasis and immune function. The delivery of MT into injured cells increased ATP levels which in turn maintained cellular bioenergetics and recovered cell functions. MSC-derived MT may be transferred tunneling nanotubes to undifferentiated cardiomyocytes and leading to their maturation. In this review, we will decipher the pathways and the mechanisms responsible for mitochondria transfer and activity. The eventual reversal of the metabolic and pro-inflammatory profile induced by the MT transfer will open new avenues for the control of inflammatory diseases.
Topics: Animals; Biomarkers; Cell Culture Techniques; Cell Differentiation; Cell- and Tissue-Based Therapy; Cellular Reprogramming; Energy Metabolism; Humans; Immunomodulation; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mitochondria; Myoblasts, Skeletal; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction
PubMed: 33763061
DOI: 10.3389/fimmu.2021.606781 -
European Journal of Medicinal Chemistry Dec 2020FF ATP synthase is responsible for the production of >95% of all ATP synthesis within the cell. Dysregulation of its expression, activity or localization is linked to... (Review)
Review
FF ATP synthase is responsible for the production of >95% of all ATP synthesis within the cell. Dysregulation of its expression, activity or localization is linked to various human diseases including cancer, diabetes, and Alzheimer's and Parkinson's disease. In addition, ATP synthase is a novel and viable drug target for the development of antimicrobials as evidenced by bedaquiline, which was approved in 2012 for the treatment of tuberculosis. Historically, natural products have been a rich source of ATP synthase inhibitors that help unravel the role of FF ATP synthase in cellular bioenergetics. During the last decade, new modulators of ATP synthase have been discovered through the isolation of novel natural products as well as through a ligand-based drug design process. In addition, new data has been obtained with regards to the structure and function of ATP synthase under physiological and pathological conditions. Crystal structure studies have provided a significant insight into the rotary function of the enzyme and may provide additional opportunities to design a new generation of inhibitors. This review provides an update on recently discovered ATP synthase modulators as well as an update on existing scaffolds.
Topics: Animals; Biological Products; Drug Design; Enzyme Inhibitors; Humans; Mitochondrial Proton-Translocating ATPases
PubMed: 32942072
DOI: 10.1016/j.ejmech.2020.112779