Search

Your search keyword '"Sana Belkhala"' showing total 4 results
Start Over Author "Sana Belkhala"
4 results on '"Sana Belkhala"'

1. Mitochondrial Complex I activity signals antioxidant response through ERK5

Author

Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Johan Garaude, Dang-Nghiem Vo, Sana Belkhala, Sabine Gerbal-Chaloin, Claire Gondeau, Martine Daujat-Chavanieu, Cécile Delettre, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Alberto Anel, José M. Cuezva, Jose A. Enriquez, Guillaume Cartron, Charles-Henri Lecellier, Javier Hernandez, and Martin Villalba

Subjects
Medicine, Science
Abstract

Abstract Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. ROS-detoxifying enzymes are made available through the activation of their antioxidant response elements (ARE) in their gene promoters. NRF2 binds to AREs and induces this anti-oxidant response. We show that cells from multiple origins performing OXPHOS induced NRF2 expression and its transcriptional activity. The NRF2 promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression. Blocking OXPHOS in a mouse model decreased Erk5 and Nrf2 expression. Furthermore, fibroblasts derived from patients with mitochondrial disorders also showed low expression of ERK5 and NRF2 mRNAs. Notably, in cells lacking functional mitochondrial complex I activity OXPHOS did not induce ERK5 expression and failed to generate this anti-oxidant response. Complex I activity induces ERK5 expression through fumarate accumulation. Eukaryotic cells have evolved a genetic program to prevent oxidative stress directly linked to OXPHOS and not requiring ROS.

Published
2018
Full Text
View/download PDF

2. Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production

Author

Abrar Ul Haq Khan, Moeez G. Rathore, Nerea Allende-Vega, Dang-Nghiem Vo, Sana Belkhala, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Guillaume Cartron, Charles-Henri Lecellier, and Martin Villalba

Subjects
Oxidative phosphorylation (OXPHOS), Mitochondria, miR-23, ERK5, MEF2, Antioxidant response elements (ARE), Medicine, Medicine (General), R5-920
Abstract

Tumor cell metabolism is altered during leukemogenesis. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. To limit the deleterious effects of excess ROS, certain gene promoters contain antioxidant response elements (ARE), e.g. the genes NQO-1 and HO-1. ROS induces conformational changes in KEAP1 and releases NRF2, which activates AREs. We show in vitro and in vivo that OXPHOS induces, both in primary leukemic cells and cell lines, de novo expression of NQO-1 and HO-1 and also the MAPK ERK5 and decreases KEAP1 mRNA. ERK5 activates the transcription factor MEF2, which binds to the promoter of the miR-23a–27a–24-2 cluster. Newly generated miR-23a destabilizes KEAP1 mRNA by binding to its 3′UTR. Lower KEAP1 levels increase the basal expression of the NRF2-dependent genes NQO-1 and HO-1. Hence, leukemic cells performing OXPHOS, independently of de novo ROS production, generate an antioxidant response to protect themselves from ROS.

Published
2016
Full Text
View/download PDF

3. Mitochondrial Complex I activity signals antioxidant response through ERK5

Author

Johan Garaude, Stefania Orecchioni, José Antonio Enríquez, Nerea Allende-Vega, Dang Nghiem Vo, Giovanna Talarico, Javier Hernandez, Sabine Gerbal-Chaloin, Abrar Ul Haq Khan, Martin Villalba, Cécile Delettre, Sana Belkhala, Claire Gondeau, Francesco Bertolini, Charles-Henri Lecellier, José M. Cuezva, Martine Daujat-Chavanieu, Alberto Anel, Guillaume Cartron, Delphine Gitenay, Ministère de l’Enseignement supérieur et de la Recherche (France), Higher Education Commission (Pakistan), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Institute of Oncology [Milan] (ESMO), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Universidad Autonoma de Madrid (UAM), Universidad Carlos III de Madrid [Madrid] (UC3M), Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Region Languedoc Roussillon, Ministere de l'Enseignement Superieur et de la Recherche (Francia), Philips, Alexandre, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Universidad Autónoma de Madrid (UAM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, STRESS, [SDV]Life Sciences [q-bio], NF-KAPPA-B, environment and public health, Oxidative Phosphorylation, PATHWAY, Mice, OXIDATIVE-PHOSPHORYLATION, ComputingMilieux_MISCELLANEOUS, GENE-EXPRESSION, Regulation of gene expression, Multidisciplinary, Chemistry, 4. Education, ACTIVATED PROTEIN-KINASE, respiratory system, Mitochondria, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Medicine, Signal transduction, Signal Transduction, Mef2, NF-E2-Related Factor 2, Mitochondrial disease, Science, Active Transport, Cell Nucleus, Oxidative phosphorylation, METABOLISM, Article, NRF2, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Antioxidant Response Elements, CANCER-CELLS, Mitogen-Activated Protein Kinase 7, Cell Nucleus, Electron Transport Complex I, Promoter, medicine.disease, MHC CLASS-I, 030104 developmental biology, Gene Expression Regulation, Cell culture, Reactive Oxygen Species
Abstract

Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. ROS-detoxifying enzymes are made available through the activation of their antioxidant response elements (ARE) in their gene promoters. NRF2 binds to AREs and induces this anti-oxidant response. We show that cells from multiple origins performing OXPHOS induced NRF2 expression and its transcriptional activity. The NRF2 promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression. Blocking OXPHOS in a mouse model decreased Erk5 and Nrf2 expression. Furthermore, fibroblasts derived from patients with mitochondrial disorders also showed low expression of ERK5 and NRF2 mRNAs. Notably, in cells lacking functional mitochondrial complex I activity OXPHOS did not induce ERK5 expression and failed to generate this anti-oxidant response. Complex I activity induces ERK5 expression through fumarate accumulation. Eukaryotic cells have evolved a genetic program to prevent oxidative stress directly linked to OXPHOS and not requiring ROS., Higher Education Commission, Pakistan (AK) and fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche (MESR) (DNV)

Published
2018
Full Text
View/download PDF

4. Human Leukemic Cells performing Oxidative Phosphorylation (OXPHOS) Generate an Antioxidant Response Independently of Reactive Oxygen species (ROS) Production

Author

Dang Nghiem Vo, Nerea Allende-Vega, Charles-Henri Lecellier, Guillaume Cartron, Moeez Ghani Rathore, Stefania Orecchioni, Giovanna Talarico, Martin Villalba, Abrar Ul Haq Khan, Francesco Bertolini, Sana Belkhala, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), European Institute of Oncology [Milan] (ESMO), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), All our funders are public or charitable organizations. This work was supported by the program 'Chercheur d'avenir' from the Region Languedoc-Roussillon (09-13195) (MV), a scientific program from the 'Communauté de Travail des Pyrénées' (CTPP5/12 to MV), the charities CIEL, L'Un pour l'Autre and Ensangble (09/2013) (MV), a grant from the European Community Program SUDOE (CLiNK SOE2/P1/E341 to MV),an AOI from the CHU Montpellier (No. 221826) (GC and MV), a grant from Fondation de France (0057921) and fellowships from the Higher Education Commission, Pakistan (MGR and AK) and Ministère de l'Enseignement Supérieur et de la Recherche (MESR) (DNV). FACsanalysis was performed at the platform Montpellier Rio Imaging (MRI). The collection of clinical data and samples (HEMODIAG_2020) at the CHRU Montpellier was supported by funding from Région Languedoc Roussillon. We thank Dr. Robert A. Hipskind for English correction of this manuscript., European Project, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Nowak, Cécile, and CLINK, SUDOE, SOE2/P1/E341 - INCOMING

Subjects
0301 basic medicine, miR-23, lcsh:Medicine, Mitochondrion, Antioxidants, Oxidative Phosphorylation, Phosphorylation, 3' Untranslated Regions, Genetics, chemistry.chemical_classification, lcsh:R5-920, Kelch-Like ECH-Associated Protein 1, Leukemia, Gene Expression Regulation, Leukemic, Intracellular Signaling Peptides and Proteins, General Medicine, GA-Binding Protein Transcription Factor, Cell biology, Mitochondria, ERK5, Bays, Organ Specificity, RNA Interference, MEF2, lcsh:Medicine (General), Research Paper, Signal Transduction, Mef2, NF-E2-Related Factor 2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oxidative phosphorylation, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Humans, Antioxidant Response Elements, RNA, Messenger, Transcription factor, Mitogen-Activated Protein Kinase 7, Reactive oxygen species, lcsh:R, Antioxidant response elements (ARE), KEAP1, MicroRNAs, Oxidative Stress, 030104 developmental biology, Oxidative phosphorylation (OXPHOS), chemistry, Gene Expression Regulation, Cell culture, Commentary, Reactive Oxygen Species
Abstract

Tumor cell metabolism is altered during leukemogenesis. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. To limit the deleterious effects of excess ROS, certain gene promoters contain antioxidant response elements (ARE), e.g. the genes NQO-1 and HO-1. ROS induces conformational changes in KEAP1 and releases NRF2, which activates AREs. We show in vitro and in vivo that OXPHOS induces, both in primary leukemic cells and cell lines, de novo expression of NQO-1 and HO-1 and also the MAPK ERK5 and decreases KEAP1 mRNA. ERK5 activates the transcription factor MEF2, which binds to the promoter of the miR-23a–27a–24-2 cluster. Newly generated miR-23a destabilizes KEAP1 mRNA by binding to its 3′UTR. Lower KEAP1 levels increase the basal expression of the NRF2-dependent genes NQO-1 and HO-1. Hence, leukemic cells performing OXPHOS, independently of de novo ROS production, generate an antioxidant response to protect themselves from ROS., Graphical abstract, Highlights • Leukemic cells performing OXPHOS increase ROS and antioxidant gene expression. • OXPHOS-mediated ERK5 activation induces miR-23 expression through MEF2. • miR-23 blocks KEAP1 expression and increases antioxidant genes. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. Excess ROS is deleterious to cells; hence they should be kept at bay. We show here that leukemic cells have a genetic program that allow them to generate an antioxidant response when performing OXPHOS and this is independent of ROS generation. Because leukemic cells need protection from ROS, this pathway is a potential target for therapeutic intervention.

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results