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The role of mitochondrial carriers in metabolic tuning and reprogramming by calcium flow across membrane contact sites

Applicant Hediger Matthias A.
Number 180326
Funding scheme Sinergia
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Interdisciplinary
Start/End 01.09.2018 - 31.08.2022
Approved amount 2'300'000.00
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All Disciplines (8)

Discipline
Interdisciplinary
Pharmacology, Pharmacy
Molecular Biology
Cellular Biology, Cytology
Physiology : other topics
Biophysics
Organic Chemistry
Biochemistry

Keywords (9)

Calcium Signalling; Cancer; Calcium regulated mitochondrial SLCs; Development Transporter Inhibitors; Store-operated calcium entry; Structures of Mitochondrial Transporters; ER-Mitochondrial Membrane Contact Sites; Regulation of Energy Metabolism; SLC Solute Carriers

Lay Summary (German)

Lead
Änderungen der intrazellulären Calciumkonzentration sind entscheidend für die Steuerung lebenswichtiger biologischer Prozesse. Wie genau sich diese Änderungen auf die Funktion der Mitochondrien auswirken, und welchen Einfluss sie auf deren Steuerung des Energiehaushalts, der Produktion von ATP (Adenosintriphosphat, Hauptenergieträger in Zellen), der metabolischen Umprogrammierung bei Krebszellen und des Zelltodes haben, soll im Detail untersucht werden.
Lay summary

Calcium-Ionen dienen als wichtige Signalmoleküle innerhalb einer Zelle und steuern eine Vielfalt von biologischen Funktionen wie Zellwachstum, Energiehaushalt, Muskelkontraktion, Immunabwehr, Befruchtung und Zelltod. Diese Signalmoleküle können als Antwort auf einen extrazellulären Stimulus aus dem Calciumspeicher des endoplasmatischen Retikulums (ER) freigesetzt werden. Zusätzlich zum ER spielen die Mitochondrien als «Energiekraftwerke» der Zellen eine wichtige Rolle bei der Calcium-abhängigen Steuerung, wobei der genaue Mechanismus noch weitgehend unbekannt ist. Insbesondere steuert Calcium in den Mitochondrien den zellulären Energiebedarf durch Regulation von Membrantransportproteinen, die sogenannten SLC Solute Carriers, welche dem Citratzyklus Substrate zur Energiegewinnung zuliefern.

Die Untersuchung dieser SLCs und deren Rolle bei der mitochondrialen Steuerung stellt das Hauptthema des Projektes dar. Da diese Steuerung bei einem Krebsbefall der Zelle häufig im Sinne einer Neuprogrammierung verändert wird, soll dies mit gezielten Eingriffen (z.B. neue Medikamente zur Krebsbehandlung) gestoppt werden.

Zur Umsetzung des Projektes wurde ein fachübergreifendes Forschungsteam mit Expertise in den Fachbereichen Strukturbiologie, Biophysik, Chemie, Elektronenmikroskopie und Krebsgenomforschung aufgebaut, um erfolgsversprechende therapeutische Ansätze schneller in die klinische Praxis zu bringen.

Direct link to Lay Summary Last update: 05.07.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells
Schild Achille, Bhardwaj Rajesh, Wenger Nicolas, Tscherrig Dominic, Kandasamy Palanivel, Dernič Jan, Baur Roland, Peinelt Christine, Hediger Matthias A., Lochner Martin (2020), Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells, in International Journal of Molecular Sciences, 21(16), 5604-5604.
Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor.
Cunha M.R., Bhardwaj R., Carrel A.L., Lindinger S., Romanin C., Parise-Filho R., Hediger M.A., Reymond J-L (2020), Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor., in RSC Med. Chem, 2020(11), 1032-1040.
Ca2+/Calmodulin Binding to STIM1 Hydrophobic Residues Facilitates Slow Ca2+-Dependent Inactivation of the Orai1 Channel
Bhardwaj Rajesh, AugustynekBartlomiej, Ercan-HerbstEbru, KandasamyPalanivel, SeedorfMatthias, PeineltChristine, HedigerMatthias A. (2020), Ca2+/Calmodulin Binding to STIM1 Hydrophobic Residues Facilitates Slow Ca2+-Dependent Inactivation of the Orai1 Channel, in Cellular Physiology and Biochemistry, 54(2), 252-270.
Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling
Pereira Gustavo José Vasco, Tavares Maurício Temotheo, Azevedo Ricardo Alexandre, Martins Barbara Behr, Cunha Micael Rodrigues, Bhardwaj Rajesh, Cury Yara, Zambelli Vanessa Olzon, Barbosa Euzébio Guimarães, Hediger Matthias A., Parise-Filho Roberto (2019), Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling, in Bioorganic & Medicinal Chemistry, 27(13), 2893-2904.

Collaboration

Group / person Country
Types of collaboration
Alexander Sobolevsky, Columbia University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Bruno Stieger, Klinik für Klinische Pharmakologie und Toxikologie, Universitätsspital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Christine Peinelt, Institute of Biochemistry and Molecular Medicine, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Irene Frischauf, JKU Life Science Center Linz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Christoph Romanin, JKU Life Science Center Linz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Swiss Physiology meeting Talk given at a conference Orai calcium channel activation mechanisms 31.08.2020 Online event, Switzerland Rajesh Bhardwaj;
European Calcium Society webinar series Individual talk Activation mechanisms of Orai channel isoforms 23.07.2020 Online event, Switzerland Rajesh Bhardwaj;
Department of Biochemistry University of Alberta Individual talk The Human SLC Solute Carrier Atlas: Structural and mechanistic diversity and new prospects for the development of tailored medicines 11.03.2020 Edmonton, Canada Hediger Matthias A.;
International Conference on Calcium Signaling – “Regulatory mechanisms to impact on health and diseases” Poster Calmodulin coordinates the slow Ca2+-dependent inactivation of the Ca2+ release-activated Ca2+ channel through STIM1 31.01.2020 Faridabad, India Kandasamy Palanivel; Augustynek Bartlomiej Stanislaw; Hediger Matthias A.; Rajesh Bhardwaj;
International Conference on Calcium Signaling – “Regulatory mechanisms to impact on health and diseases” Talk given at a conference Calmodulin coordinates the slow Ca2+-dependent inactivation of the Ca2+ release-activated Ca2+ channel through STIM1 31.01.2020 Faridabad, India Rajesh Bhardwaj;
EMBO Symposium on Calcium signaling – “Molecular mechanisms to role in health and diseases” Talk given at a conference Exploring Orai channel gating mechanisms using different constitutively active Orai mutants 26.01.2020 Bangalore, India Rajesh Bhardwaj;
EMBO Symposium on Calcium signaling – “Molecular mechanisms to role in health and diseases” Poster Exploring Orai channel gating mechanisms using different constitutively active Orai mutants 26.01.2020 Bangalore, India Hediger Matthias A.; Rajesh Bhardwaj; Gyimesi Gergely; Augustynek Bartlomiej Stanislaw;
EMBO Symposium on Calcium signaling – “Molecular mechanisms to role in health and diseases” Poster Ca2+/calmodulin coordinates slow Ca2+-dependent inactivation of the Ca2+release-activated Ca2+ channel through STIM1 26.01.2020 Bangalore, India Hediger Matthias A.; Rajesh Bhardwaj; Augustynek Bartlomiej Stanislaw; Kandasamy Palanivel;
Norwegian Biochemical Society Meeting Talk given at a conference Structure and transport mechanism of mitochondrial carriers 23.01.2020 Voss, Norway Kunji Edmund;
The Crick Institute Individual talk Refuelling the eukaryotic cell: How ADP and ATP cross the mitochondrial inner membrane 15.01.2020 London, Great Britain and Northern Ireland Kunji Edmund;
Bunty plot meeting Talk given at a conference Energetics of ADP/ATP exchange 14.11.2019 London, Great Britain and Northern Ireland Kunji Edmund;
The Day of BioMedical Research Poster Oncogenic driver mutations dictate the increased amino acid consumption in colorectal cancer cells by upregulating the amino acid transporters through Hippo signalling 13.11.2019 Bern, Switzerland Kandasamy Palanivel; Pujol Gimenez Jonai; Nydegger Damian; Zlobec Inti; Rajesh Bhardwaj; Hediger Matthias A.;
Citrin Deficiency meeting Talk given at a conference Understanding the molecular basis of citrin deficiency 11.11.2019 Singapore, Singapore Kunji Edmund;
Biochemical Society Meeting Talk given at a conference Thermostability assays for membrane protein optimization 04.11.2019 London, Great Britain and Northern Ireland Kunji Edmund;
MRC London Institute of Medical Sciences Individual talk Refuelling the eukaryotic cell: How ADP and ATP cross the mitochondrial inner membrane 08.10.2019 London, Great Britain and Northern Ireland Kunji Edmund;
60th Congress of the Italian Society of Biochemistry and Molecular Biology Talk given at a conference Fundamentals and importance of the SLC solute carrier superfamily and future perspectives 18.09.2019 Lecce, Italy Hediger Matthias A.;
Fall Meeting of the Swiss Chemical Society Poster Diverse effects of halogenated 2-aminoethoxydiphenyl borate derivatives on store-operated calcium entry in breast cancer cells 06.09.2019 Zurich, Switzerland Lochner Martin; Hediger Matthias A.; Schild Achille; Rajesh Bhardwaj;
85th Harden Conference Dynamic Membrane Complexes: Respiration and Transport Talk given at a conference Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier 29.08.2019 Bonn, Germany Kunji Edmund;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster SLC-pharma: A proposal for a new service to effectively determine ligand affinities to SLC solute carrier drug targets 04.08.2019 Luzern, Switzerland Clemencon Benjamin; Hediger Matthias A.;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster Identifying new small molecule inhibitors for the mitochondrial pyruvate carrier 04.08.2019 Luzern, Switzerland Kunji Edmund;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster The role of mitochondrial carriers in metabolic tuning and reprogramming by calcium flow across membrane contact sites 04.08.2019 Luzern, Switzerland Nydegger Damian; Rajesh Bhardwaj; Augustynek Bartlomiej Stanislaw; Kunji Edmund; Lochner Martin; Hediger Matthias A.;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster Role of amino acid transporters and their regulatory mechanisms in colorectal cancer progression 04.08.2019 Luzern, Switzerland Nydegger Damian; Zlobec Inti; Hediger Matthias A.; Rajesh Bhardwaj; Pujol Gimenez Jonai; Kandasamy Palanivel;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster The extended SLC atlas 04.08.2019 Luzern, Switzerland Hediger Matthias A.; Gyimesi Gergely;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Talk given at a conference The extended SLC Atlas: Towards a unified view 04.08.2019 Luzern, Switzerland Gyimesi Gergely;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster Understanding the constitutive activity of the ANSGA mutant of human Orai1 channel 04.08.2019 Luzern, Switzerland Rajesh Bhardwaj; Hediger Matthias A.; Gyimesi Gergely;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster Ca2+/calmodulin coordinates slow Ca2+-dependent inactivation of the Ca2+ release-activated Ca2+ channel through STIM1 04.08.2019 Luzern, Switzerland Hediger Matthias A.; Rajesh Bhardwaj; Kandasamy Palanivel; Augustynek Bartlomiej Stanislaw;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Talk given at a conference The molecular basis of diseases caused by dysfunctional mitochondrial carriers 04.08.2019 Luzern, Switzerland Kunji Edmund;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Poster Distinct effects of 2-APB derivatives on store-operated calcium entry and calcium mobilization in MDA-MB-231 and MCF-7 breast cancer cells 04.08.2019 Luzern, Switzerland Augustynek Bartlomiej Stanislaw; Lochner Martin; Rajesh Bhardwaj; Hediger Matthias A.; Kandasamy Palanivel; Schild Achille;
BioMedical Transporters Conference – “Membrane transporters and channels: From basic research to drug development and clinical application” Talk given at a conference Calcium-dependent inactivation of the calcium releaseactivated calcium (CRAC) channel 04.08.2019 Luzern, Switzerland Rajesh Bhardwaj;


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
Video/Film Activation mechanisms of Orai channel isoforms International 2020

Associated projects

Number Title Start Funding scheme
198281 New insights into the COVID-19 pandemic: Genetic polymorphisms, role of SLC6 amino acid transporters, renal aspects and therapeutic perspectives 01.11.2020 NRP 78 Covid-19
160782 Store-operated calcium channels in health and disease 01.10.2015 Sinergia
204972 Modulation of calcium influx by Orai channel isoforms and pharmaceutical interventions 01.11.2021 Project funding (Div. I-III)
182272 Intestinal absorption of transition metals in human health and disease 01.02.2019 Project funding (Div. I-III)

Abstract

Intracellular Ca2+ signals control an array of physiological functions including gene expression, cell proliferation, muscle contraction and fertilization and are central to regulating cell death and survival. These Ca2+ signals arise from the release of Ca2+ from endoplasmic reticulum (ER) stores, followed by activation of a refilling pathway known as store-operated Ca2+ entry (SOCE) and/or other Ca2+ influx routes through the plasma membrane (PM), such as epithelial Ca2+ channel TRPV6. The spatiotemporal patterning of Ca2+ signals and the localization of Ca2+-dependent effectors ensure their specific translation into physiological responses. The highly dynamic nature of ER and membrane tethering proteins allows ER to establish transient physical contacts with PM, mitochondria and other organelles and thereby shape the spatiotemporal patterns of Ca2+ signals. The release of Ca2+ at the membrane contact sites (MCS) enable the formation of microdomains of high Ca2+ concentrations also called Ca2+ hotspots between these closely apposed organellar membranes, for example ER-mitochondria (ER-Mt) contact sites. Ca2+ hotspots on the mitochondrial surface facilitate the function of mitochondrial Ca2+ uniporter (MCU) to take up Ca2+ despite its low affinity to Ca2+. Ca2+ signaling is linked to bioenergetic homeostasis, which ensures that energy supply has the capacity to meet energy demand. A rise in intracellular Ca2+ concentration signals an increased cellular energy demand, which in part is also required for the efficient functioning of Ca2+ ATPases crucial for maintaining Ca2+ homeostasis. Despite significant progress in our understanding of how Ca2+ signaling is coupled to energy metabolism, there are still many crucial missing links that we aim to address in this grant application: 1. The role of ER-Mt contact sites and the MCU complex in promoting bioenergetics has been established, because a rise in mitochondrial matrix Ca2+ concentration drives the allosteric activation of the rate-limiting enzymes of the tricarboxylic acid cycle. In addition, several SLC mitochondrial solute carriers are regulated by cytosolic Ca2+ levels and are likely to be involved in this process. It is, however, unknown whether Ca2+-regulated mitochondrial solute carriers (mSLCsCa) are localized in ER-Mt contact sites and whether the bioenergetic function of mSLCsCa is directly modulated by the dynamics of ER-Mt contact sites (WP1, WP2 and WP3). 2. SOCE has also been implicated in regulating mitochondrial bioenergetics. However, the mechanistic basis and the molecular links other than MCU are not clear (WP2 and WP3). 3. It is intriguing to hypothesize that subplasmalemmal mitochondria being in close vicinity to TRPV6 channels at the PM augment bioenergetics through a direct impact on MCU and mSLCsCa, which could explain the role of TRPV6 in prostate and breast cancer progression (WP3). 4. It is largely unknown whether mSLCsCa contribute in a feedback mechanism to the regulation of MCS and the associated Ca2+ flow, thereby affecting Ca2+ homeostasis (WP4). 5. The SOCE machinery and the ER-to-mitochondria Ca2+ transferring machinery are remodeled in several cancer types (partly by the role of oncogenes), with serious consequences on biosynthetic pathways. However, how oncogene and tumor suppressor mutations affect the expression and function of mSLCsCa and whether altered Ca2+ flow across MCS is also linked to dysregulation of mSLCsCa remains elusive (WP5). 6. Structural details on the conformational changes induced by Ca2+ in several mSLCsCa are either entirely missing or partly understood and these studies are essential to understand the Ca2+ regulation mechanism of mSLCsCa-mediated transport (WP6). Thus, the overall purpose of this proposal is to investigate the role of Ca2+ flow across MCS in regulating the bioenergetic function of mSLCsCa in cell physiology and how this contributes to the metabolic reprogramming in cancer. To achieve these goals, we have assembled an interdisciplinary research team that integrates state-of-the-art structural biology, membrane biophysics, synthetic chemistry, super-resolution imaging, electron microscopy and next-generation cancer tissue microarray analysis.
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