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1دورية أكاديمية
المؤلفون: Dina Baier, Theresa Mendrina, Beatrix Schoenhacker‐Alte, Christine Pirker, Thomas Mohr, Mate Rusz, Benedict Regner, Martin Schaier, Nicolas Sgarioto, Noël J.‐M. Raynal, Karin Nowikovsky, Wolfgang M. Schmidt, Petra Heffeter, Samuel M. Meier‐Menches, Gunda Koellensperger, Bernhard K. Keppler, Walter Berger
المصدر: Advanced Science, Vol 10, Iss 32, Pp n/a-n/a (2023)
مصطلحات موضوعية: BOLD‐100, chemoresistance, histone acetylation, lactate transporter, lipid metabolism, mitochondrial respiration, Science
الوصف: Abstract The leading first‐in‐class ruthenium‐complex BOLD‐100 currently undergoes clinical phase‐II anticancer evaluation. Recently, BOLD‐100 is identified as anti‐Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD‐100‐resistant colon and pancreatic carcinoma cells. Acute BOLD‐100 treatment reduces lipid droplet contents of BOLD‐100‐sensitive but not ‐resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD‐100‐resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame‐shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl‐coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell‐free BOLD‐100‐CoA adduct formation suggesting acetyl‐CoA depletion as mechanism bridging BOLD‐100‐induced lipid metabolism alterations and histone acetylation‐mediated gene expression deregulation. Indeed, BOLD‐100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de‐acetylation as central mode‐of‐action of BOLD‐100 and metabolic programs stabilizing histone acetylation as relevant Achilles’ heel of acquired BOLD‐100‐resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD‐100 responsiveness. Summarizing, BOLD‐100 is identified as epigenetically active substance acting via targeting several onco‐metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD‐100 resistance opens novel strategies to tackle therapy failure.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2198-3844Test
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2دورية أكاديمية
المؤلفون: Shane Austin, Mojtaba Tavakoli, Christina Pfeiffer, Julia Seifert, Andrea Mattarei, Diego De Stefani, Mario Zoratti, Karin Nowikovsky
المصدر: Frontiers in Physiology, Vol 8 (2017)
مصطلحات موضوعية: LETM1, mitochondrial cation/proton exchange, mitochondrial volume homeostasis, potassium, sodium, calcium, Physiology, QP1-981
الوصف: Ca2+ transport across the inner membrane of mitochondria (IMM) is of major importance for their functions in bioenergetics, cell death and signaling. It is therefore tightly regulated. It has been recently proposed that LETM1—an IMM protein with a crucial role in mitochondrial K+/H+ exchange and volume homeostasis—also acts as a Ca2+/H+ exchanger. Here we show for the first time that lowering LETM1 gene expression by shRNA hampers mitochondrial K+/H+ and Na+/H+ exchange. Decreased exchange activity resulted in matrix K+ accumulation in these mitochondria. Furthermore, LETM1 depletion selectively decreased Na+/Ca2+ exchange mediated by NCLX, as observed in the presence of ruthenium red, a blocker of the Mitochondrial Ca2+ Uniporter (MCU). These data confirm a key role of LETM1 in monovalent cation homeostasis, and suggest that the effects of its modulation on mitochondrial transmembrane Ca2+ fluxes may reflect those on Na+/H+ exchange activity.
وصف الملف: electronic resource
العلاقة: http://journal.frontiersin.org/article/10.3389/fphys.2017.00839/fullTest; https://doaj.org/toc/1664-042XTest
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3دورية أكاديمية
المؤلفون: Pauline Dao (Research Platform Rhythms of Life, Research Platforms, University of Vienna), Stefan Hajny (Research Platform Rhythms of Life, Research Platforms, University of Vienna), Ronald Mekis (Department of Internal Medicine I, Medical University Vienna), Lukas Orel (Research Platform Rhythms of Life, Research Platforms, University of Vienna), Nora Dinhopl (Department of Pathobiology, Institute of Pathology, University of Veterinary Medicine Vienna), Kristin Tessmar-Raible (Research Platform Rhythms of Life, Research Platforms, University of Vienna), Karin Nowikovsky (Department of Internal Medicine I, Medical University Vienna)
المصدر: Life Science Alliance ; issn:2575-1077
مصطلحات موضوعية: Health, Toxicology and Mutagenesis, Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous), Ecology
الوصف: The abstract is available here: https://uscholar.univie.ac.at/o:1674710Test ; The abstract is available here: https://uscholar.univie.ac.at/o:1674710Test
وصف الملف: application/pdf
العلاقة: hdl:11353/10.1674710; https://phaidra.univie.ac.at/o:1674710Test
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المؤلفون: Walter Berger, Bernhard K. Keppler, Petra Heffeter, Rosa Lemmens-Gruber, Christian R. Kowol, Sushilla Schoonhoven, Nastasia Wilfinger, Karin Nowikovsky, Thomas Schöfl, Martin Holcmann, Gernot Walko, Theresa Tuder, Johannes Gojo, Ute Jungwirth
الوصف: Supplementary Figure 1. Role of p53 status and mitochondrial membrane depolarization in KP46-induced cell death Supplementary Figure 2. Expression and localization changes of pro- and anti-apoptotic Bcl-2 family members in response to KP46 treatment Supplementary Figure 3. Impact or KP46 on integrin β1 expression and subcellular localization in cancer cells Supplementary Figure 4. Alteration in intracellular Ca2+ levels in HCT-116 cells upon KP46 treatment Supplementary Figure 5 Effect of extracellular calpain inhibition on KP46 sensitivity in A427 and HCT-116 cells
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::06c123ee3f1856c4a99f4b622607524aTest
https://doi.org/10.1158/1535-7163.22501641.v1Test -
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المؤلفون: Walter Berger, Bernhard K. Keppler, Petra Heffeter, Rosa Lemmens-Gruber, Christian R. Kowol, Sushilla Schoonhoven, Nastasia Wilfinger, Karin Nowikovsky, Thomas Schöfl, Martin Holcmann, Gernot Walko, Theresa Tuder, Johannes Gojo, Ute Jungwirth
الوصف: On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan–caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax- but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-β1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg–Gly–Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg2+ ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpain-mediated mechanism as a novel mode of action for the anticancer gallium compound KP46. Mol Cancer Ther; 13(10); 2436–49. ©2014 AACR.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::737c5cf131165fd711e4d6e63f47a4c9Test
https://doi.org/10.1158/1535-7163.c.6536850.v1Test -
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المؤلفون: Shane Austin, Ronald Mekis, Sami E M Mohammed, Mariafrancesca Scalise, Wen‐An Wang, Michele Galluccio, Christina Pfeiffer, Tamara Borovec, Katja Parapatics, Dijana Vitko, Nora Dinhopl, Nicolas Demaurex, Keiryn L Bennett, Cesare Indiveri, Karin Nowikovsky
المصدر: EMBO reports. 23
مصطلحات موضوعية: Genetics, Molecular Biology, Biochemistry
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::c31fb41744affc4162681f7b4e0cad79Test
https://doi.org/10.15252/embr.202254978Test -
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المؤلفون: Shane, Austin, Ronald, Mekis, Sami E M, Mohammed, Mariafrancesca, Scalise, Wen-An, Wang, Michele, Galluccio, Christina, Pfeiffer, Tamara, Borovec, Katja, Parapatics, Dijana, Vitko, Nora, Dinhopl, Nicolas, Demaurex, Keiryn L, Bennett, Cesare, Indiveri, Karin, Nowikovsky
المصدر: EMBO reports. 23(12)
الوصف: Mitochondrial Ca
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::f80598a8e0024d8b677e7752b50baa61Test
https://pubmed.ncbi.nlm.nih.gov/36321428Test -
8دورية أكاديمية
المؤلفون: Sonja Hager (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Katharina Korbula (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Björn Bielec (Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna), Michael Grusch (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Christine Pirker (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Markus Schosserer (Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences), Lisa Liendl (Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences), Magdalena Lang (Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences), Johannes Grillari (Department of Biotechnology, BOKU-University of Natural Resources and Life Sciences), Karin Nowikovsky (Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna), Veronika F. S. Pape (Department of Physiology, Faculty of Medicine, Semmelweis University), Thomas Mohr (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Gergely Szakács (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Bernhard K. Keppler (Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna), Walter Berger (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna), Christian R. Kowol (Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna), Petra Heffeter (Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna)
المصدر: Cell Death & Disease
الوصف: The abstract is available here: https://uscholar.univie.ac.at/o:1030459Test
وصف الملف: application/pdf
العلاقة: isPartOf:https://phaidra.univie.ac.at/o:243553Test[u:scholar collection]; hdl:11353/10.1030459; https://phaidra.univie.ac.at/o:1030459Test
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المؤلفون: Rauan Kaiyrzhanov, Sami E.M. Mohammed, Reza Maroofian, Ralf A. Husain, Alessia Catania, Alessandra Torraco, Ahmad Alahmad, Marina Dutra-Clarke, Sabine Grønborg, Annapurna Sudarsanam, Julie Vogt, Filippo Arrigoni, Julia Baptista, Shahzad Haider, René G. Feichtinger, Paolo Bernardi, Alessandra Zulian, Mirjana Gusic, Stephanie Efthymiou, Renkui Bai, Farah Bibi, Alejandro Horga, Julian A. Martinez-Agosto, Amanda Lam, Andreea Manole, Diego-Perez Rodriguez, Romina Durigon, Angela Pyle, Buthaina Albash, Carlo Dionisi-Vici, David Murphy, Diego Martinelli, Enrico Bugiardini, Katrina Allis, Costanza Lamperti, Siegfried Reipert, Lotte Risom, Lucia Laugwitz, Michela Di Nottia, Robert McFarland, Laura Vilarinho, Michael Hanna, Holger Prokisch, Johannes A. Mayr, Enrico Silvio Bertini, Daniele Ghezzi, Elsebet Østergaard, Saskia B. Wortmann, Rosalba Carrozzo, Tobias B. Haack, Robert W. Taylor, Antonella Spinazzola, Karin Nowikovsky, Henry Houlden
المصدر: Am. J. Hum. Genet. 109, 1692-1712 (2022)
Kaiyrzhanov, R, Mohammed, S E M, Maroofian, R, Husain, R A, Catania, A, Torraco, A, Alahmad, A, Dutra-Clarke, M, Grønborg, S, Sudarsanam, A, Vogt, J, Arrigoni, F, Baptista, J, Haider, S, Feichtinger, R G, Bernardi, P, Zulian, A, Gusic, M, Efthymiou, S, Bai, R, Bibi, F, Horga, A, Martinez-Agosto, J A, Lam, A, Manole, A, Rodriguez, D P, Durigon, R, Pyle, A, Albash, B, Dionisi-Vici, C, Murphy, D, Martinelli, D, Bugiardini, E, Allis, K, Lamperti, C, Reipert, S, Risom, L, Laugwitz, L, Di Nottia, M, McFarland, R, Vilarinho, L, Hanna, M, Prokisch, H, Mayr, J A, Bertini, E S, Ghezzi, D, Østergaard, E, Wortmann, S B, Carrozzo, R, Haack, T B, Taylor, R W, Spinazzola, A, Nowikovsky, K & Houlden, H 2022, ' Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement ', American Journal of Human Genetics, vol. 109, no. 9, pp. 1692-1712 . https://doi.org/10.1016/j.ajhg.2022.07.007Test
American Journal of Human Genetics, 109, 9, pp. 1692-1712
American Journal of Human Genetics, 109, 1692-1712مصطلحات موضوعية: Mitochondrial Diseases, oxidative phosphorylation, LETM1, Wolf-Hirschhorn syndrome, genetics, mitochondria, mitochondrial diseases, neurodegeneration, neurology, potassium transport, volume homeostasis, Homeostasis, Humans, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Nervous System, Saccharomyces cerevisiae, Calcium-Binding Proteins, Genetics (clinical), Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Doenças Genéticas, Settore MED/03 - Genetica Medica, Settore MED/26 - Neurologia, Genetics, Letm1, Neurodegeneration, Neurology, Oxidative Phosphorylation, Potassium Transport, Volume Homeostasis, Wolf-hirschhorn Syndrome
الوصف: Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies. This research was supported using resources of the Core Facility Cell Imaging and Ultrastructure Research, University of Vienna, a member of the Vienna Life-Science Instruments (VLSI) and the VetCore Facility (Imaging) of the University of Veterinary Medicine Vienna. We acknowledge International Centre for Genomic Medicine in Neuromuscular Diseases. This research was funded in part, by the Wellcome Trust (WT093205MA, WT104033AIA, and the Synaptopathies Strategic Award, 165908). This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetrees Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research United Kingdom, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy United Kingdom (MDUK), Muscular Dystrophy Association (MDA USA) and Senior Non-Clinical Fellow ship to A. Spinazzola, (MC_PC_13029). K.N. and S.E.M.M. were supported by the Austrian Science Funds FWF-P29077 and P31471. A. Spinazzola receives support also from The Lily Foun dation and Brain Research UK. R.K. was supported by European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042). info:eu-repo/semantics/publishedVersion
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c3335fe5e93e6a1aab34ba05806a590Test
https://pubmed.ncbi.nlm.nih.gov/36055214Test -
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المؤلفون: Keiryn L. Bennett, Karin Nowikovsky, Mariafrancesca Scalise, Michele Galluccio, Shane Austin, Tamara Borovec, Cesare Indiveri, Sami E. M. Mohammed, Nora Dinhopl, Dijana Vitko, Christina Pfeiffer, Katja Parapatics, Ronald Mekis
مصطلحات موضوعية: Cytosol, Programmed cell death, Chemistry, TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY, Antiporter, Transporter, LETM1, Mitochondrion, Interactome, Homeostasis, Cell biology
الوصف: Mitochondrial Ca2+ ions are crucial regulators of bioenergetics, cell death pathways and cytosolic Ca2+ homeostasis. Mitochondrial Ca2+ content strictly depends on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+/H+ exchanger (CHE). Originally identified as the mitochondrial K+/H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identified MICS1, the only mitochondrial member of the TMBIM family. Applying cell-based and cell-free biochemical assays, here we demonstrate that MICS1 is responsible for the Na+- and permeability transition pore-independent mitochondrial Ca2+ release and identify MICS1 as the long-sought mitochondrial CHE. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::eef5fffd5c6e3ed8141b19c23498b28eTest
https://doi.org/10.1101/2021.11.11.468204Test