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Article: Editorial: Novel Strategies in Drug Development Against Multifactorial Diseases.

Esposito, Cinzia / Johansson, Catrine / Di Micco, Simone

2022 Volume 10, Page(s) 838063

Language	English
Publishing date	2022-01-24
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2022.838063
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: How phosphorylation and ATPase activity regulate anion flux through the cystic fibrosis transmembrane conductance regulator (CFTR).

Zwick, Matthias / Esposito, Cinzia / Hellstern, Manuel / Seelig, Anna

The Journal of biological chemistry

2016 Volume 291, Issue 46, Page(s) 23928

Language	English
Publishing date	2016-11-10
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.A116.721415
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Article ; Online: How Phosphorylation and ATPase Activity Regulate Anion Flux though the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Zwick, Matthias / Esposito, Cinzia / Hellstern, Manuel / Seelig, Anna

The Journal of biological chemistry

2016 Volume 291, Issue 28, Page(s) 14483–14498

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), mutations of which cause cystic fibrosis, belongs to the ATP-binding cassette (ABC) transporter family and works as a channel for small anions, such as chloride and bicarbonate. Anion ...

Abstract	The cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), mutations of which cause cystic fibrosis, belongs to the ATP-binding cassette (ABC) transporter family and works as a channel for small anions, such as chloride and bicarbonate. Anion channel activity is known to depend on phosphorylation by cAMP-dependent protein kinase A (PKA) and CFTR-ATPase activity. Whereas anion channel activity has been extensively investigated, phosphorylation and CFTR-ATPase activity are still poorly understood. Here, we show that the two processes can be measured in a label-free and non-invasive manner in real time in live cells, stably transfected with CFTR. This study reveals three key findings. (i) The major contribution (≥90%) to the total CFTR-related ATP hydrolysis rate is due to phosphorylation by PKA and the minor contribution (≤10%) to CFTR-ATPase activity. (ii) The mutant CFTR-E1371S that is still conductive, but defective in ATP hydrolysis, is not phosphorylated, suggesting that phosphorylation requires a functional nucleotide binding domain and occurs in the post-hydrolysis transition state. (iii) CFTR-ATPase activity is inversely related to CFTR anion flux. The present data are consistent with a model in which CFTR is in a closed conformation with two ATPs bound. The open conformation is induced by ATP hydrolysis and corresponds to the post-hydrolysis transition state that is stabilized by phosphorylation and binding of chloride channel potentiators.
MeSH term(s)	Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Anions/metabolism ; Catalysis ; Cell Line ; Cricetinae ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Glycolysis ; Hydrolysis ; Mutation ; Oxidative Phosphorylation
Chemical Substances	Anions ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Adenosine Triphosphate (8L70Q75FXE) ; Adenosine Triphosphatases (EC 3.6.1.-)
Language	English
Publishing date	2016-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.721415
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Article ; Online: Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids.

Harter, Marius F / Recaldin, Timothy / Gerard, Regine / Avignon, Blandine / Bollen, Yannik / Esposito, Cinzia / Guja-Jarosz, Karolina / Kromer, Kristina / Filip, Adrian / Aubert, Julien / Schneider, Anneliese / Bacac, Marina / Bscheider, Michael / Stokar-Regenscheit, Nadine / Piscuoglio, Salvatore / Beumer, Joep / Gjorevski, Nikolche

Nature biomedical engineering

2023 Volume 8, Issue 4, Page(s) 345–360

Abstract: Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal ... ...

Abstract	Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence. We found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune-epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
MeSH term(s)	Antibodies, Bispecific/immunology ; Antibodies, Bispecific/pharmacology ; Humans ; Organoids/immunology ; T-Lymphocytes/immunology ; Apoptosis ; Intestines/immunology ; Immunotherapy/methods ; Epithelial Cell Adhesion Molecule/immunology ; Neoplasms/immunology ; Neoplasms/therapy ; Female ; Intestinal Mucosa/immunology
Chemical Substances	Antibodies, Bispecific ; Epithelial Cell Adhesion Molecule
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-023-01156-5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Corrigendum: VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function.

Briston, Thomas / Stephen, Jenna M / Thomas, Luke W / Esposito, Cinzia / Chung, Yuen-Li / Syafruddin, Saiful E / Turmaine, Mark / Maddalena, Lucas A / Greef, Basma / Szabadkai, Gyorgy / Maxwell, Patrick H / Vanharanta, Sakari / Ashcroft, Margaret

Frontiers in oncology

2021 Volume 11, Page(s) 740273

Abstract: This corrects the article DOI: 10.3389/fonc.2018.00388.]. ...

Abstract	[This corrects the article DOI: 10.3389/fonc.2018.00388.].
Language	English
Publishing date	2021-09-23
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.740273
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia.

Thomas, Luke W / Esposito, Cinzia / Morgan, Rachel E / Price, Stacey / Young, Jamie / Williams, Steven P / Maddalena, Lucas A / McDermott, Ultan / Ashcroft, Margaret

Communications biology

2021 Volume 4, Issue 1, Page(s) 615

Abstract: Mitochondria are typically essential for the viability of eukaryotic cells, and utilize oxygen and nutrients (e.g. glucose) to perform key metabolic functions that maintain energetic homeostasis and support proliferation. Here we provide a comprehensive ... ...

Abstract	Mitochondria are typically essential for the viability of eukaryotic cells, and utilize oxygen and nutrients (e.g. glucose) to perform key metabolic functions that maintain energetic homeostasis and support proliferation. Here we provide a comprehensive functional annotation of mitochondrial genes that are essential for the viability of a large panel (625) of tumour cell lines. We perform genome-wide CRISPR/Cas9 deletion screening in normoxia-glucose, hypoxia-glucose and normoxia-galactose conditions, and identify both unique and overlapping genes whose loss influences tumour cell viability under these different metabolic conditions. We discover that loss of certain oxidative phosphorylation (OXPHOS) genes (e.g. SDHC) improves tumour cell growth in hypoxia-glucose, but reduces growth in normoxia, indicating a metabolic switch in OXPHOS gene function. Moreover, compared to normoxia-glucose, loss of genes involved in energy-consuming processes that are energetically demanding, such as translation and actin polymerization, improve cell viability under both hypoxia-glucose and normoxia-galactose. Collectively, our study defines mitochondrial gene essentiality in tumour cells, highlighting that essentiality is dependent on the metabolic environment, and identifies routes for regulating tumour cell viability in hypoxia.
MeSH term(s)	CRISPR-Cas Systems ; Cell Proliferation ; Genes, Mitochondrial ; Genome, Mitochondrial ; Glycolysis ; Humans ; Hypoxia/physiopathology ; Mitochondria/genetics ; Mitochondria/pathology ; Neoplasms/genetics ; Neoplasms/pathology ; Oxidative Phosphorylation ; Tumor Cells, Cultured
Language	English
Publishing date	2021-05-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-02098-x
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Article: CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain.

Thomas, Luke W / Stephen, Jenna M / Esposito, Cinzia / Hoer, Simon / Antrobus, Robin / Ahmed, Afshan / Al-Habib, Hasan / Ashcroft, Margaret

Cancer & metabolism

2019 Volume 7, Page(s) 2

Abstract: Background: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required ...

Abstract	Background: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is critical for regulating intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of Results: Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS). Conclusions: Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology.
Language	English
Publishing date	2019-03-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2700141-6
ISSN	2049-3002
ISSN	2049-3002
DOI	10.1186/s40170-019-0194-y
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Article: CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism.

Thomas, Luke W / Esposito, Cinzia / Stephen, Jenna M / Costa, Ana S H / Frezza, Christian / Blacker, Thomas S / Szabadkai, Gyorgy / Ashcroft, Margaret

Cancer & metabolism

2019 Volume 7, Page(s) 7

Abstract: Background: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that ... ...

Abstract	Background: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved. Results: Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that Conclusions: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells.
Language	English
Publishing date	2019-07-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2700141-6
ISSN	2049-3002
ISSN	2049-3002
DOI	10.1186/s40170-019-0200-4
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Article: Dynamic sorting of lipids and proteins in membrane tubes with a moving phase boundary

Heinrich, Michael / Tian, Aiwei / Esposito, Cinzia / Baumgart, Tobias

Proceedings of the National Academy of Sciences of the United States of America. 2010 Apr. 20, v. 107, no. 16

2010

Abstract: Cellular organelle membranes maintain their integrity, global shape, and composition despite vigorous exchange among compartments of lipids and proteins during trafficking and signaling. Organelle homeostasis involves dynamic molecular sorting mechanisms ...

Abstract	Cellular organelle membranes maintain their integrity, global shape, and composition despite vigorous exchange among compartments of lipids and proteins during trafficking and signaling. Organelle homeostasis involves dynamic molecular sorting mechanisms that are far from being understood. In contrast, equilibrium thermodynamics of membrane mixing and sorting, particularly the phase behavior of binary and ternary model membrane mixtures and its coupling to membrane mechanics, is relatively well characterized. Elucidating the continuous turnover of live cell membranes, however, calls for experimental and theoretical membrane models enabling manipulation and investigation of directional mass transport. Here we introduce the phenomenon of curvature-induced domain nucleation and growth in membrane mixtures with fluid phase coexistence. Membrane domains were consistently observed to nucleate precisely at the junction between a strongly curved cylindrical (tube) membrane and a pipette-aspirated giant unilamellar vesicle. This experimental geometry mimics intracellular sorting compartments, because they often show tubular-vesicular membrane regions. Nucleated domains at tube necks were observed to present diffusion barriers to the transport of lipids and proteins. We find that curvature-nucleated domains grow with characteristic parabolic time dependence that is strongly curvature-dependent. We derive an analytical model that reflects the observed growth dynamics. Numerically calculated membrane shapes furthermore allow us to elucidate mechanical details underlying curvature-dependent directed lipid transport. Our observations suggest a novel dynamic membrane sorting principle that may contribute to intracellular protein and lipid sorting and trafficking.
Keywords	cell membranes ; homeostasis ; lipids ; mass transfer ; membrane proteins ; mixing ; models ; thermodynamics
Language	English
Dates of publication	2010-0420
Size	p. 7208-7213.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0913997107
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Dynamic sorting of lipids and proteins in membrane tubes with a moving phase boundary.

Heinrich, Michael / Tian, Aiwei / Esposito, Cinzia / Baumgart, Tobias

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 16, Page(s) 7208–7213

Abstract	Cellular organelle membranes maintain their integrity, global shape, and composition despite vigorous exchange among compartments of lipids and proteins during trafficking and signaling. Organelle homeostasis involves dynamic molecular sorting mechanisms that are far from being understood. In contrast, equilibrium thermodynamics of membrane mixing and sorting, particularly the phase behavior of binary and ternary model membrane mixtures and its coupling to membrane mechanics, is relatively well characterized. Elucidating the continuous turnover of live cell membranes, however, calls for experimental and theoretical membrane models enabling manipulation and investigation of directional mass transport. Here we introduce the phenomenon of curvature-induced domain nucleation and growth in membrane mixtures with fluid phase coexistence. Membrane domains were consistently observed to nucleate precisely at the junction between a strongly curved cylindrical (tube) membrane and a pipette-aspirated giant unilamellar vesicle. This experimental geometry mimics intracellular sorting compartments, because they often show tubular-vesicular membrane regions. Nucleated domains at tube necks were observed to present diffusion barriers to the transport of lipids and proteins. We find that curvature-nucleated domains grow with characteristic parabolic time dependence that is strongly curvature-dependent. We derive an analytical model that reflects the observed growth dynamics. Numerically calculated membrane shapes furthermore allow us to elucidate mechanical details underlying curvature-dependent directed lipid transport. Our observations suggest a novel dynamic membrane sorting principle that may contribute to intracellular protein and lipid sorting and trafficking.
MeSH term(s)	1,2-Dipalmitoylphosphatidylcholine/chemistry ; Biological Transport ; Computer Simulation ; Lipids/chemistry ; Lipids/physiology ; Microscopy, Atomic Force/methods ; Models, Biological ; Models, Statistical ; Phosphatidylcholines/chemistry ; Protein Transport ; Proteins/chemistry ; Signal Transduction ; Thermodynamics
Chemical Substances	Lipids ; Phosphatidylcholines ; Proteins ; 1,2-Dipalmitoylphosphatidylcholine (2644-64-6) ; 1,2-oleoylphosphatidylcholine (EDS2L3ODLV)
Language	English
Publishing date	2010-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0913997107
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