179 results on '"Rossignol Rodrigue"'
Search Results
152. Analyse bioénergétique et moléculaire de la physiopathologie du Syndrome de Costello
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DARD, Laetitia, Rossignol, Rodrigue, Nouette-Gaulain, Karine, Sonveaux, Pierre, Djouadi, Fatima, and Kluza, Jérôme
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MiR-221 ,Syndrome de Costello ,Protéine Kinase activée par l'AMP (AMPK) ,Biogenèse ,HRAS ,Mitochondries
153. Regulation of energy metabolism : study of Bioenergetics remodeling in cancer
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Obre, Emilie, Rossignol, Rodrigue, Rumjanek, Flanklin Reza, Bouzier-Sore, Anne-Karine, Arsac, Laurent, Sonveaux, Pierre, Kluza, Jérôme, and STAR, ABES
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Bioenergetics remodeling ,Glucose deprivation ,Métabolisme énergétique ,Serine metabolism ,Glucose déprivation ,Remodelage métabolique ,Energy metabolism ,Mitochondrie ,Métabolisme de la sérine ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Mitochondria - Abstract
This thesis investigates the metabolic remodeling of cancer cells. Three models are analyzed by different biochemical and genetic approaches: (i) lung cells transduced with oncogenic HRASG12V, (ii) HeLa cells challenged with glucose deprivation and (iii) surgical pieces of lung tumors. On each model the observed metabolic remodeling involves numerous catabolic and anabolic pathways, including glutaminolysis and serine biosynthesis. Our work revealed an important role of mitochondria in metabolic remodeling, both for the supply of energy and for the synthesis of antioxidants and amino acids, but also phospholipids. We show the extent of a single mutation HRASG12V on a very large number of metabolic processes, revealing the importance of genetics in the metabolic remodeling of cancer cells. However, glucose deprivation also induced a remarkable remodeling at many levels of cell metabolism, from the splicing of messenger RNAs to serine biosynthesis. In the third part, this thesis identified two bioenergetic classes of lung tumors, opening interesting opportunities for the diagnosis and understanding of this type of tumor, but also to propose appropriate therapeutic strategies. The results identify biomarkers and targets validated in our in vitro models. The outlook of this thesis will be to the implementation of these approaches in the clinic, Cette thèse étudie le remodelage métabolique des cellules cancéreuses. Trois modèles sont analysés par de nombreuses approches biochimiques et génétiques : (i) des cellules de poumon transduites avec une forme oncogénique de HRASG12V, (ii) des cellules HeLa soumises à une privation de glucose et (iii) des pièces chirurgicales de cancer du poumon. Sur chaque modèle, le remodelage métabolique observé met en jeu de nombreuses voies du catabolisme et de l’anabolisme, notamment la glutaminolyse et la biosynthèse de sérine. Ce travail révèle un rôle important des mitochondries dans ce remodelage, à la fois pour l’apport d’énergie et pour la synthèse d’antioxydants et d’acides aminés, mais aussi de phospholipides. J’ai montré l’impact étendu d’une simple mutation HRASG12V sur un très grand nombre de processus, révélant ainsi l’importance de la génétique dans le remodelage métabolique des cellules cancéreuses. Toutefois, la privation de glucose induit elle aussi un remarquable remodelage à de très nombreux niveaux, depuis l’épissage des ARN messagers jusqu’à la synthèse de sérine. Enfin, cette thèse identifie deux classes bioénergétiques de tumeurs du poumon, ouvrant de nombreuses perspectives pour le diagnostic et la compréhension de ce type de tumeurs, mais aussi pour proposer des stratégies thérapeutiques adaptées. Les résultats identifient des biomarqueurs et des cibles validées sur nos modèles in vitro. Les perspectives de cette thèse vont consister à la transposition de ces approches à la clinique.
154. Bioénergétique des tumeurs : impact de l'hypoxie et de l'aglycémie sur le métabolisme énergétique du cancer du sein
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SMOLKOVA, Katarina, Rossignol, Rodrigue, Jezek, Petr, Kraml, Jiri, Modriansky, Martin, and Villalba, Martin
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Protéines découplantes ,Apoptose ,Métabolisme énergétique ,Mitochondries ,Cancer
155. Rôles des mitochondries dans la tumorigenèse : implications dans le traitement du cancer
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JOSE, Caroline, Rossignol, Rodrigue, Bouzier-Sore, Anne-Karine, Capdevila, Xavier, Mazurier, Frederic, Simonnet, Helene, and Villalba, Martin
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Bioénergétique ,Mitochondries ,Stratégies thérapeutiques ,Remodelage métabolique ,Oxydations phosphorylantes ,Cancer
156. The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.
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Pierpont EI, Bennett AM, Schoyer L, Stronach B, Anschutz A, Borrie SC, Briggs B, Burkitt-Wright E, Castel P, Cirstea IC, Draaisma F, Ellis M, Fear VS, Frone MN, Flex E, Gelb BD, Green T, Gripp KW, Khoshkhoo S, Kieran MW, Kleemann K, Klein-Tasman BP, Kontaridis MI, Kruszka P, Leoni C, Liu CZ, Merchant N, Magoulas PL, Moertel C, Prada CE, Rauen KA, Roelofs R, Rossignol R, Sevilla C, Sevilla G, Sheedy R, Stieglitz E, Sun D, Tiemens D, White F, Wingbermühle E, Wolf C, Zenker M, and Andelfinger G
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- Humans, ras Proteins genetics, MAP Kinase Signaling System genetics, Costello Syndrome genetics, Neoplasms genetics, Ectodermal Dysplasia genetics, Noonan Syndrome genetics, Heart Defects, Congenital genetics
- Abstract
Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2024
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157. Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling.
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Esteves P, Blanc L, Celle A, Dupin I, Maurat E, Amoedo N, Cardouat G, Ousova O, Gales L, Bellvert F, Begueret H, Thumerel M, Dupuy JW, Desbenoit N, Marthan R, Girodet PO, Rossignol R, Berger P, and Trian T
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- Bronchi, Fatty Acids metabolism, Humans, Muscle, Smooth, Oxidation-Reduction, Asthma metabolism, Proteomics
- Abstract
Background: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since mitochondria produce the highest levels of cellular energy and fatty acid β-oxidation is the most powerful way to produce ATP, we hypothesised that, in asthmatic BSM cells, energetic metabolism is shifted towards the β-oxidation of fatty acids., Objectives: We aimed to characterise BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation., Methods: 21 asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using matrix-assisted laser desorption/ionisation spectrometry imaging., Results: Asthmatic BSM cells were characterised by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo . Proteome remodelling of asthmatic BSM occurred via two canonical mitochondrial pathways. The levels of carnitine palmitoyl transferase (CPT)2 and low-density lipoprotein (LDL) receptor, which internalise fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL receptor drastically and specifically reduced asthmatic BSM cell proliferation., Conclusion: This study demonstrates a metabolic switch towards mitochondrial β-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma., Competing Interests: Conflict of interest: P. Esteves reports other (postdoctoral salary) from Fondation pour la Recherche Médicale, grants from Fondation Bordeaux université (FGLMR/AVAD), during the conduct of the study. Conflict of interest: L. Blanc reports other (salary) from Fondation pour la Recherche Médicale, during the conduct of the study. Conflict of interest: A. Celle has nothing to disclose. Conflict of interest: I. Dupin has a delivered patent (EP 15152886 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease”), and a submitted patent (EP 20173595.8 “New compositions and methods of treating COVID-19 disease”), all outside the submitted work. Conflict of interest: E. Maurat has nothing to disclose. Conflict of interest: N. Amoedo has nothing to disclose. Conflict of interest: G. Cardouat has nothing to disclose. Conflict of interest: O. Ousova has nothing to disclose. Conflict of interest: L. Gales has nothing to disclose. Conflict of interest: F. Bellvert has nothing to disclose. Conflict of interest: H. Begueret has nothing to disclose. Conflict of interest: M. Thumerel has nothing to disclose. Conflict of interest: J-W. Dupuy has nothing to disclose. Conflict of interest: N. Desbenoit has nothing to disclose. Conflict of interest: R. Marthan has nothing to disclose. Conflict of interest: P-O. Girodet reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Chiesi, GlaxoSmithKline, Novartis and Sanofi, outside the submitted work. Conflict of interest: R. Rossignol has nothing to disclose. Conflict of interest: P. Berger reports grants from Fondation pour la Recherche Médicale, during the conduct of the study; grants and personal fees from Novartis, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Chiesi, AstraZeneca and Sanofi, non-financial support from Menarinni and TEVA, outside the submitted work; and has a patent EP 15152886.6 “New compositions and methods of treating and/or preventing chronic obstructive pulmonary disease” issued, a patent 22605-FR “Geometric characterization of airways using MRI” pending, and a patent EP 20173595.8 “New compositions and methods of treating COVID-19 disease” pending. Conflict of interest: T. Trian reports grants from Agence Nationale pour la Recherche, during the conduct of the study., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)
- Published
- 2021
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158. Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics.
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Molino D, Pila-Castellanos I, Marjault HB, Dias Amoedo N, Kopp K, Rochin L, Karmi O, Sohn YS, Lines L, Hamaï A, Joly S, Radreau P, Vonderscher J, Codogno P, Giordano F, Machin P, Rossignol R, Meldrum E, Arnoult D, Ruggieri A, Nechushtai R, de Chassey B, and Morel E
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- Homeostasis, Humans, Iron, Mitochondria, Mitochondrial Proteins genetics
- Abstract
Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER-mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research., (© 2020 The Authors.)
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- 2020
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159. Targeting Human Lung Adenocarcinoma with a Suppressor of Mitochondrial Superoxide Production.
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Dias Amoedo N, Dard L, Sarlak S, Mahfouf W, Blanchard W, Rousseau B, Izotte J, Claverol S, Lacombe D, Rezvani HR, Pierri CL, and Rossignol R
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- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung pathology, Cyclic N-Oxides metabolism, Electron Transport Complex I metabolism, Humans, Adenocarcinoma of Lung etiology, Adenocarcinoma of Lung metabolism, Mitochondria metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, Signal Transduction
- Abstract
Aims: REDOX signaling from reactive oxygen species (ROS) generated by the mitochondria (mitochondrial reactive oxygen species [mtROS]) has been implicated in cancer growth and survival. Here, we investigated the effect of 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione (AOL), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics, and growth. Results: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo . Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and increased the expression of the complex I subunit NDUFV1 which was also identified as AOL binding site using molecular modeling computer simulations. Comparison of the molecular changes induced by AOL and MitoTEMPO, an mtROS scavenger that is not an S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets. Innovation: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Lastly, our study revealed the repression of NDUFV1 by S1QEL AOL. Conclusion: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling.
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- 2020
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160. Mitochondria Participate in Chemoresistance to Cisplatin in Human Ovarian Cancer Cells.
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Zampieri LX, Grasso D, Bouzin C, Brusa D, Rossignol R, and Sonveaux P
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- Animals, Autophagy, Bridged-Ring Compounds administration & dosage, Carcinoma virology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm, Female, Humans, Mice, Nude, Mitochondria metabolism, Mitophagy, Ovarian Neoplasms virology, Oxidation-Reduction, Taxoids administration & dosage, Antineoplastic Agents pharmacology, Carcinoma drug therapy, Cisplatin pharmacology, Energy Metabolism, Ovarian Neoplasms drug therapy, Signal Transduction
- Abstract
Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of cases, a majority of them discontinues treatment owing to side effects and to the emergence of resistance. In this study, we focused on resistance to cisplatin and investigated whether metabolic changes could be involved. As models, we used matched pairs of cisplatin-sensitive (SKOV-3 and COV-362) and cisplatin-resistant (SKOV-3-R and COV-362-R) human ovarian carcinoma cells that were selected in vitro following exposure to increasing doses of the chemotherapy. Metabolic comparison revealed that resistant cells undergo a shift toward a more oxidative metabolism. The shift goes along with a reorganization of the mitochondrial network, with a generally increased mitochondrial compartment. More functional mitochondria in cisplatin-resistant compared with cisplatin-sensitive cells were associated to enzymatic changes affecting either the electron transport chain (SKOV-3/SKOV-3-R model) or mitochondrial coupling (COV-362/COV-362-R model). Our findings further indicate that the preservation of functional mitochondria in these cells could be due to an increased mitochondrial turnover rate, suggesting mitophagy inhibition as a potential strategy to tackle cisplatin-resistant human ovarian cancer progression. IMPLICATIONS: Besides classical mechanisms related to drug efflux and target modification, we report that preserving functional mitochondria is a strategy used by human ovarian cancer cells to resist to cisplatin chemotherapy., (©2020 American Association for Cancer Research.)
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- 2020
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161. Doxorubicin Inhibits Phosphatidylserine Decarboxylase and Modifies Mitochondrial Membrane Composition in HeLa Cells.
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Bellance N, Furt F, Melser S, Lalou C, Thoraval D, Maneta-Peyret L, Lacombe D, Moreau P, and Rossignol R
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- Carboxy-Lyases antagonists & inhibitors, Cardiotoxicity etiology, Cardiotoxicity genetics, Cardiotoxicity pathology, Cell Death drug effects, Doxorubicin adverse effects, HeLa Cells, Humans, Mitochondrial Membranes enzymology, Neoplasms complications, Neoplasms drug therapy, Neoplasms pathology, Phosphatidylethanolamines metabolism, Phosphatidylserines metabolism, Carboxy-Lyases genetics, Doxorubicin pharmacology, Mitochondrial Membranes drug effects, Neoplasms genetics
- Abstract
Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, mostly in pediatric cases. Here, we demonstrate that DXR alters the mitochondrial membrane composition associated with bioenergetic impairment and cell death in human cancer cells. The remodeling of the mitochondrial membrane was explained by phosphatidylserine decarboxylase (PSD) inhibition by DXR. PSD catalyzes phosphatidylethanolamine (PE) synthesis from phosphatidylserine (PS), and DXR altered the PS/PE ratio in the mitochondrial membrane. Moreover, we observed that DXR localized to the mitochondrial compartment and drug uptake was rapid. Evaluation of other topoisomerase II inhibitors did not show any impact on the mitochondrial membrane composition, indicating that the DXR effect was specific. Therefore, our findings revealed a side molecular target for DXR and PSD, potentially involved in DXR anti-cancer properties and the associated toxicity.
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- 2020
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162. Nuclear control of lung cancer cells migration, invasion and bioenergetics by eukaryotic translation initiation factor 3F.
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Esteves P, Dard L, Brillac A, Hubert C, Sarlak S, Rousseau B, Dumon E, Izotte J, Bonneu M, Lacombe D, Dupuy JW, Amoedo N, and Rossignol R
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- A549 Cells, Adenocarcinoma of Lung metabolism, Adenocarcinoma of Lung pathology, Animals, Cell Movement drug effects, Cell Movement genetics, Cell Nucleus genetics, Cell Nucleus pathology, Datasets as Topic, Energy Metabolism drug effects, Eukaryotic Initiation Factor-3 genetics, Gene Knockdown Techniques, HeLa Cells, Humans, Hydroxybenzoates pharmacology, Lung cytology, Lung pathology, Lung Neoplasms metabolism, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Mice, Mutation, Neoplasm Invasiveness genetics, Nitrofurans pharmacology, Oxidative Phosphorylation drug effects, RNA, Small Interfering metabolism, RNA-Seq, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor genetics, Snail Family Transcription Factors genetics, Survival Analysis, Xenograft Model Antitumor Assays, Adenocarcinoma of Lung genetics, Cell Nucleus metabolism, Energy Metabolism genetics, Eukaryotic Initiation Factor-3 metabolism, Gene Expression Regulation, Neoplastic, Lung Neoplasms genetics, STAT3 Transcription Factor metabolism
- Abstract
The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein-protein and the protein-DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.
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- 2020
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163. UVB-induced DHODH upregulation, which is driven by STAT3, is a promising target for chemoprevention and combination therapy of photocarcinogenesis.
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Hosseini M, Dousset L, Michon P, Mahfouf W, Muzotte E, Bergeron V, Bortolotto D, Rossignol R, Moisan F, Taieb A, Bouzier-Sore AK, and Rezvani HR
- Abstract
The leading cause of cutaneous squamous cell carcinomas (cSCCs) is exposure to ultraviolet radiation (UV). Unlike most other cancers, the incidence rates of cSCCs are still on the rise and the treatment options currently available are limited. We have recently found that dihydroorotate dehydrogenase (DHODH), which is the rate-limiting enzyme in the de novo pyrimidine synthesis pathway, plays a critical role in UVB-induced energy metabolism reprogramming. Using a multistage model of UVB radiation-induced skin cancer, we show that UVB-induced DHODH upregulation is mainly regulated transcriptionally by STAT3. Our results indicate that chronic inhibition of DHODH by leflunomide (LFN) blocks UVB-induced tumor initiation. Human tumor xenograft studies showed that LFN treatment reduces growth of established tumors when used in combination with a genotoxic agent, 5-fluorouracil (5-FU). Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.
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- 2019
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164. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.
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Gentric G, Kieffer Y, Mieulet V, Goundiam O, Bonneau C, Nemati F, Hurbain I, Raposo G, Popova T, Stern MH, Lallemand-Breitenbach V, Müller S, Cañeque T, Rodriguez R, Vincent-Salomon A, de Thé H, Rossignol R, and Mechta-Grigoriou F
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- Animals, Cell Line, Tumor, Female, Humans, Mice, Mice, Nude, Oxidative Phosphorylation, Oxidative Stress, Carcinoma metabolism, Mitochondria metabolism, Ovarian Neoplasms metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha physiology, Promyelocytic Leukemia Protein physiology
- Abstract
High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1α axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1α. Active PGC-1α increases synthesis of electron transport chain complexes, thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1α-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2019
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165. Energy Metabolism Rewiring Precedes UVB-Induced Primary Skin Tumor Formation.
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Hosseini M, Dousset L, Mahfouf W, Serrano-Sanchez M, Redonnet-Vernhet I, Mesli S, Kasraian Z, Obre E, Bonneu M, Claverol S, Vlaski M, Ivanovic Z, Rachidi W, Douki T, Taieb A, Bouzier-Sore AK, Rossignol R, and Rezvani HR
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- Animals, DNA-Binding Proteins metabolism, Dihydroorotate Dehydrogenase, Down-Regulation radiation effects, Electron Transport radiation effects, Epidermis pathology, Epidermis radiation effects, Glutamine metabolism, High Mobility Group Proteins metabolism, Keratinocytes metabolism, Keratinocytes pathology, Keratinocytes radiation effects, Metabolic Networks and Pathways, Mice, Mice, Hairless, Oxidoreductases Acting on CH-CH Group Donors metabolism, Phenotype, Up-Regulation radiation effects, Carcinogenesis metabolism, Carcinogenesis radiation effects, Energy Metabolism radiation effects, Skin Neoplasms metabolism, Skin Neoplasms pathology, Ultraviolet Rays
- Abstract
Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2018
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166. Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation.
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Lavie J, Serrat R, Bellance N, Courtand G, Dupuy JW, Tesson C, Coupry I, Brice A, Lacombe D, Durr A, Stevanin G, Darios F, Rossignol R, Goizet C, and Bénard G
- Subjects
- Animals, Cells, Cultured, Dynamins, Female, Humans, Male, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Mice, Neurons pathology, Phosphoprotein Phosphatases genetics, Phosphoprotein Phosphatases metabolism, Phosphorylation genetics, Cell Nucleus genetics, Cell Nucleus metabolism, Cell Nucleus pathology, GTP Phosphohydrolases genetics, GTP Phosphohydrolases metabolism, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Mitochondria metabolism, Mitochondria pathology, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Neurons metabolism, Spastic Paraplegia, Hereditary metabolism, Spastic Paraplegia, Hereditary pathology
- Abstract
Hereditary spastic paraplegia, SPG31, is a rare neurological disorder caused by mutations in REEP1 gene encoding the microtubule-interacting protein, REEP1. The mechanism by which REEP1-dependent processes are linked with the disease is unclear. REEP1 regulates the morphology and trafficking of various organelles via interaction with the microtubules. In this study, we collected primary fibroblasts from SPG31 patients to investigate their mitochondrial morphology. We observed that the mitochondrial morphology in patient cells was highly tubular compared with control cells. We provide evidence that these morphological alterations are caused by the inhibition of mitochondrial fission protein, DRP1, due to the hyperphosphorylation of its serine 637 residue. This hyperphosphorylation is caused by impaired interactions between REEP1 and mitochondrial phosphatase PGAM5. Genetically or pharmacologically induced decrease of DRP1-S637 phosphorylation restores mitochondrial morphology in patient cells. Furthermore, ectopic expression of REEP1 carrying pathological mutations in primary neuronal culture targets REEP1 to the mitochondria. Mutated REEP1 proteins sequester mitochondria to the perinuclear region of the neurons and therefore, hamper mitochondrial transport along the axon. Considering the established role of mitochondrial distribution and morphology in neuronal health, our results support the involvement of a mitochondrial dysfunction in SPG31 pathology., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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167. Redox Homeostasis and Mitochondrial Dynamics.
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Willems PH, Rossignol R, Dieteren CE, Murphy MP, and Koopman WJ
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- Animals, Humans, Mitochondria pathology, Oxidation-Reduction, Mitochondria metabolism, Reactive Nitrogen Species metabolism, Reactive Oxygen Species metabolism, Signal Transduction
- Abstract
Within living cells, mitochondria are considered relevant sources of reactive oxygen species (ROS) and are exposed to reactive nitrogen species (RNS). During the last decade, accumulating evidence suggests that mitochondrial (dys)function, ROS/RNS levels, and aberrations in mitochondrial morphology are interconnected, albeit in a cell- and context-dependent manner. Here it is hypothesized that ROS and RNS are involved in the short-term regulation of mitochondrial morphology and function via non-transcriptional pathways. We review the evidence for such a mechanism and propose that it allows homeostatic control of mitochondrial function and morphology by redox signaling., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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168. Rheb regulates mitophagy induced by mitochondrial energetic status.
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Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, and Bénard G
- Subjects
- Animals, Autophagy physiology, HeLa Cells, Humans, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mitochondria metabolism, Mitochondrial Membranes metabolism, Monomeric GTP-Binding Proteins metabolism, Oxidative Phosphorylation, Mitochondria physiology, Mitochondrial Proteins metabolism, Mitophagy physiology
- Abstract
Mitophagy has been recently described as a mechanism of elimination of damaged organelles. Although the regulation of the amount of mitochondria is a core issue concerning cellular energy homeostasis, the relationship between mitochondrial degradation and energetic activity has not yet been considered. Here, we report that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. Upon high oxidative phosphorylation activity, we found that the small GTPase Rheb is recruited to the mitochondrial outer membrane. This mitochondrial localization of Rheb promotes mitophagy through a physical interaction with the mitochondrial autophagic receptor Nix and the autophagosomal protein LC3-II. Thus, Rheb-dependent mitophagy contributes to the maintenance of optimal mitochondrial energy production. Our data suggest that mitochondrial degradation contributes to a bulk renewal of the organelle in order to prevent mitochondrial aging and to maintain the efficiency of oxidative phosphorylation., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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169. Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function.
- Author
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Martin J, Maurhofer O, Bellance N, Benard G, Graber F, Hahn D, Galinier A, Hora C, Gupta A, Ferrand G, Hoppeler H, Rossignol R, Dufour JF, and St-Pierre MV
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Glutamate Dehydrogenase metabolism, Hepatocytes metabolism, Hepatocytes pathology, Hydrolases deficiency, Hydrolases genetics, Hydrolases physiology, Lipid Metabolism physiology, Liver pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Proteins deficiency, Mitochondrial Proteins genetics, Mitochondrial Proteins physiology, Models, Animal, Reactive Oxygen Species metabolism, Blood Glucose metabolism, Liver metabolism, Mitochondria, Liver physiology
- Abstract
Unlabelled: The histidine triad nucleotide-binding (HINT2) protein is a mitochondrial adenosine phosphoramidase expressed in the liver and pancreas. Its physiological function is unknown. To elucidate the role of HINT2 in liver physiology, the mouse Hint2 gene was deleted. Hint2(-/-) and Hint2(+/+) mice were generated in a mixed C57Bl6/J × 129Sv background. At 20 weeks, the phenotypic changes in Hint2(-/-) relative to Hint2(+/+) mice were an accumulation of hepatic triglycerides, decreased tolerance to glucose, a defective counter-regulatory response to insulin-provoked hypoglycemia, and an increase in plasma interprandial insulin but a decrease in glucose-stimulated insulin secretion and defective thermoregulation upon fasting. Leptin messenger RNA (mRNA) in adipose tissue and plasma leptin were elevated. In mitochondria from Hint2(-/-) hepatocytes, state 3 respiration was decreased, a finding confirmed in HepG2 cells where HINT2 mRNA was silenced. The linked complex II-III electron transfer was decreased in Hint2(-/-) mitochondria, which was accompanied by a lower content of coenzyme Q. Hypoxia-inducible factor-2α expression and the generation of reactive oxygen species were increased. Electron microscopy of mitochondria in Hint2(-/-) mice aged 12 months revealed clustered, fused organelles. The hepatic activities of 3-hydroxyacyl-coenzyme A dehydrogenase short chain and glutamate dehydrogenase (GDH) were decreased by 68% and 60%, respectively, without a change in protein expression. GDH activity was similarly decreased in HINT2-silenced HepG2 cells. When measured in the presence of purified sirtuin 3, latent GDH activity was recovered (126% in Hint2(-/-) versus 83% in Hint2(+/+) ). This suggests a greater extent of acetylation in Hint2(-/-) than in Hint2(+/+) ., Conclusion: Hint2/HINT2 positively regulates mitochondrial lipid metabolism and respiration and glucose homeostasis. The absence of Hint2 provokes mitochondrial deformities and a change in the pattern of acetylation of selected proteins., (Copyright © 2012 American Association for the Study of Liver Diseases.)
- Published
- 2013
- Full Text
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170. Local anesthetic 'in-situ' toxicity during peripheral nerve blocks: update on mechanisms and prevention.
- Author
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Nouette-Gaulain K, Capdevila X, and Rossignol R
- Subjects
- Anesthetics, Local toxicity, Energy Metabolism drug effects, Humans, Intraoperative Complications prevention & control, Mitochondria, Muscle drug effects, Mitochondria, Muscle pathology, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal pathology, Muscle Fibers, Skeletal ultrastructure, Neurons drug effects, Neurons pathology, Neurons ultrastructure, Anesthetics, Local adverse effects, Nerve Block adverse effects, Peripheral Nerves
- Abstract
Purpose of Review: Peripheral nerve blocks induce undesired side-effects linked to the toxicity of local anesthetics on neuron and myocytes via different cell targets. The effects of local anesthetics on these targets are now well known and summarized in this review., Recent Findings: Local anesthetic-induced local cell toxicity involved different pathways leading to cell death, necrosis and different factors closely associated with the clinical practice modulated this toxicity. High concentration and prolonged duration of local anesthetic administration are closely associated with severe lesions., Summary: Phenotypic analyses revealed that local anesthetics could induce histological damage with lesions ranging from local to extreme in skeletal muscle. Metabolic alterations were also described involving sarcoplasmic reticulum and calcium dysregulation, alteration of mitochondrial physiology and of oxidative phosphorylation with associated overproduction of harmful reactive oxygen species, typically leading to apoptosis or necrosis. Biochemical and cell biology investigations now indicate that local anesthetics interact with different molecular targets in mammalian cells as respiratory chain complex I or the prosurvival kinase Akt. Functional dysfunction in both muscle and neuron remains to be investigated with caution in patients, as local anesthetic toxicity remains under-evaluated. Likewise, the use of adapted local anesthetics in patients with particular diseases and neuromuscular disorder could further reduce the risk of undesired effect.We need to improve our practice, and the optimization of our clinical protocol could prevent from these side-effects. Lastly, experimental studies highlight the preventive effects of antioxidant drugs or of recombinant human erythropoietin but the pharmacokinetic feature of such strategies remain to be evaluated.
- Published
- 2012
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171. REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.
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Goizet C, Depienne C, Benard G, Boukhris A, Mundwiller E, Solé G, Coupry I, Pilliod J, Martin-Négrier ML, Fedirko E, Forlani S, Cazeneuve C, Hannequin D, Charles P, Feki I, Pinel JF, Ouvrard-Hernandez AM, Lyonnet S, Ollagnon-Roman E, Yaouanq J, Toutain A, Dussert C, Fontaine B, Leguern E, Lacombe D, Durr A, Rossignol R, Brice A, and Stevanin G
- Subjects
- Adolescent, Adult, Aged, Base Sequence, Child, Child, Preschool, Energy Metabolism, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Mutation Rate, Pedigree, Phenotype, Sequence Deletion, Spastic Paraplegia, Hereditary metabolism, Young Adult, Membrane Transport Proteins genetics, Mitochondria metabolism, Mutation, Spastic Paraplegia, Hereditary genetics
- Abstract
Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver-like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain., (© 2011 Wiley-Liss, Inc.)
- Published
- 2011
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172. Bioenergetics of cancer. Foreword.
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Rossignol R
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use, Humans, Metabolic Networks and Pathways genetics, Mitochondria metabolism, Mitochondria physiology, Molecular Targeted Therapy methods, Neoplasms genetics, Neoplasms physiopathology, Precision Medicine methods, Precision Medicine trends, Energy Metabolism physiology, Neoplasms metabolism
- Published
- 2011
- Full Text
- View/download PDF
173. XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas.
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Rezvani HR, Kim AL, Rossignol R, Ali N, Daly M, Mahfouf W, Bellance N, Taïeb A, de Verneuil H, Mazurier F, and Bickers DR
- Subjects
- Animals, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Proliferation, DNA Damage, DNA Repair, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Energy Metabolism, Gene Knockdown Techniques, Gene Silencing, Humans, Keratinocytes pathology, Keratinocytes transplantation, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria metabolism, Models, Biological, Mutation, NADPH Oxidase 1, NADPH Oxidases genetics, NADPH Oxidases metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Transplantation, Heterologous, Carcinoma, Squamous Cell etiology, Cell Transformation, Neoplastic genetics, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Keratinocytes metabolism, Skin Neoplasms etiology
- Abstract
DNA damage is a well-known initiator of tumorigenesis. Studies have shown that most cancer cells rely on aerobic glycolysis for their bioenergetics. We sought to identify a molecular link between genomic mutations and metabolic alterations in neoplastic transformation. We took advantage of the intrinsic genomic instability arising in xeroderma pigmentosum C (XPC). The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies. In cultured human keratinocytes, we showed that lentivirus-mediated knockdown of XPC reduced mitochondrial oxidative phosphorylation and increased glycolysis, recapitulating cancer cell metabolism. Accumulation of unrepaired DNA following XPC silencing increased DNA-dependent protein kinase activity, which subsequently activated AKT1 and NADPH oxidase-1 (NOX1), resulting in ROS production and accumulation of specific deletions in mitochondrial DNA (mtDNA) over time. Subcutaneous injection of XPC-deficient keratinocytes into immunodeficient mice led to squamous cell carcinoma formation, demonstrating the tumorigenic potential of transduced cells. Conversely, simultaneous knockdown of either NOX1 or AKT1 blocked the neoplastic transformation induced by XPC silencing. Our results demonstrate that genomic instability resulting from XPC silencing results in activation of AKT1 and subsequently NOX1 to induce ROS generation, mtDNA deletions, and neoplastic transformation in human keratinocytes.
- Published
- 2011
- Full Text
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174. Time course of mitochondrial metabolism alterations to repeated injections of bupivacaine in rat muscle.
- Author
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Nouette-Gaulain K, Bringuier S, Canal-Raffin M, Bernard N, Lopez S, Dadure C, Masson F, Mercier J, Sztark F, Rossignol R, and Capdevila X
- Subjects
- Adenosine Diphosphate administration & dosage, Anesthetics, Local administration & dosage, Animals, Bupivacaine administration & dosage, Citrate (si)-Synthase drug effects, Citrate (si)-Synthase metabolism, Electron Transport drug effects, Male, Mitochondria, Muscle metabolism, Muscular Diseases chemically induced, Muscular Diseases physiopathology, Oxygen Consumption drug effects, Polarography, Psoas Muscles drug effects, Psoas Muscles metabolism, Rats, Rats, Wistar, Time Factors, Anesthetics, Local toxicity, Bupivacaine toxicity, Energy Metabolism drug effects, Mitochondria, Muscle drug effects
- Abstract
Purpose: Bupivacaine-induced myotoxicity is associated with mitochondrial bioenergetic alterations. The impact of the duration of bupivacaine treatment on mitochondrial energy production remains undetermined. Here, we assessed, in vivo, the alteration of mitochondrial metabolism following different durations of bupivacaine exposure (40, 56, or 112 hr) that correspond to 5, 7, or 14 repeated injections of 0.25% bupivacaine, respectively., Methods: Rats were divided randomly into seven different groups: one control group (no catheter); three groups with normal saline injections (1 mL x kg(-1)) every eight hours via a femoral nerve catheter for 40, 56, and 112 hr, respectively; and three groups with 0.25% bupivacaine injections (1 mL x kg(-1)) every eight hours via a femoral nerve catheter for 40, 56, and 112 hr. Psoas and gracilis muscle samples located within the bupivacaine infusion-diffusion space were investigated. To estimate mitochondrial respiratory capacity, the protein content of the mitochondrial respiratory chain apparatus was evaluated by measuring citrate synthase activity. To measure mitochondrial respiratory function, adenosine diphosphate-stimulated oxygen consumption was measured by polarography in saponin-skinned muscle fibres using glutamate-malate or succinate as energy substrates., Results: In psoas and gracilis muscles, saline solution had no effect on the two mitochondrial parameters. Bupivacaine induced a significant decrease in the citrate synthase activity in psoas (r(2) = 0.74; P < 0.001) and gracilis muscle (r(2) = 0.52; P < 0.001), and there was a significant decrease in the adenosine diphosphate-stimulated oxygen consumption using glutamate or succinate as substrates in both muscles (P < 0.001)., Conclusions: The severity of bupivacaine-induced myotoxicity is closely linked to the duration of bupivacaine exposure in the muscle fibres located close to the catheter tip.
- Published
- 2010
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175. Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia.
- Author
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Smolková K, Bellance N, Scandurra F, Génot E, Gnaiger E, Plecitá-Hlavatá L, Jezek P, and Rossignol R
- Subjects
- Adaptation, Physiological, Breast cytology, Breast metabolism, Breast Neoplasms pathology, Cell Hypoxia physiology, Cell Line, Cell Line, Tumor, Cell Survival, Energy Metabolism, Female, Humans, Models, Biological, Oxidative Phosphorylation, Oxygen Consumption, Breast Neoplasms metabolism, Glucose metabolism, Mitochondria metabolism
- Abstract
Breast cancer cells can survive and proliferate under harsh conditions of nutrient deprivation, including limited oxygen and glucose availability. We hypothesized that such environments trigger metabolic adaptations of mitochondria, which promote tumor progression. Here, we mimicked aglycemia and hypoxia in vitro and compared the mitochondrial and cellular bioenergetic adaptations of human breast cancer (HTB-126) and non-cancer (HTB-125) cells that originate from breast tissue. Using high-resolution respirometry and western blot analyses, we demonstrated that 4 days of glucose deprivation elevated oxidative phosphorylation five-fold, increased the spread of the mitochondrial network without changing its shape, and decreased the apparent affinity of oxygen in cancer cells (increase in C ( 50 )), whereas it remained unchanged in control cells. The substrate control ratios also remained constant following adaptation. We also observed the Crabtree effect, specifically in HTB-126 cells. Likewise, sustained hypoxia (1% oxygen during 6 days) improved cell respiration in non-cancer cells grown in glucose or glucose-deprived medium (+ 32% and +38%, respectively). Conversely, under these conditions of limited oxygen or a combination of oxygen and glucose deprivation for 6 days, routine respiration was strongly reduced in cancer cells (-36% in glucose medium, -24% in glucose-deprived medium). The data demonstrate that cancer cells behave differently than normal cells when adapting their bioenergetics to microenvironmental conditions. The differences in hypoxia and aglycemia tolerance between breast cancer cells and non-cancer cells may be important when optimizing strategies for the treatment of breast cancer.
- Published
- 2010
- Full Text
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176. Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis.
- Author
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Bellance N, Lestienne P, and Rossignol R
- Subjects
- DNA, Mitochondrial genetics, Energy Metabolism, Gene Expression, Humans, Mutation, Signal Transduction, Cell Transformation, Neoplastic, Mitochondria metabolism, Neoplasms metabolism
- Abstract
In this review, we discuss the concept of metabolic remodeling and signaling in tumors, specifically the various metabolites that participate in the regulation of gene expression in cancer cells. In particular, pyruvate, oxaloacetate, succinate and fumarate, four mitochondrial metabolites, activate genes relevant for tumor progression. When the balance between glycolysis and oxidative phosphorylation is altered, these metabolites accumulate in the cytoplasm and regulate the activity of the Hypoxia Inducible Factor 1alpha (HIF-1alpha). HIF is one of the main factors that orchestrate the metabolic switch observed during oncogenesis. There is also an important role for lactate, fructose 1-6 bisphosphate or citrate that leads to the diversion of glucose metabolites to anabolism. In addition reactive oxygen species, which are produced by the respiratory chain, could serve as an endogenous source of DNA-damaging agents to promote genetic instability. Accordingly, several mitochondrial DNA mutations were reported in tumors, and the construction of cybrids recently demonstrated their role in the control of tumor progression.
- Published
- 2009
- Full Text
- View/download PDF
177. Mitochondrial fluidity matters. Focus on "Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria".
- Author
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Benard G and Rossignol R
- Subjects
- Diffusion, Electron Transport Complex I genetics, Electron Transport Complex I metabolism, Extracellular Matrix Proteins metabolism, Humans, Mitochondria enzymology, Electron Transport Complex I deficiency, Mitochondria physiology
- Published
- 2008
- Full Text
- View/download PDF
178. Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases.
- Author
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Rocher C, Taanman JW, Pierron D, Faustin B, Benard G, Rossignol R, Malgat M, Pedespan L, and Letellier T
- Subjects
- Animals, Computer Simulation, Humans, Cell Physiological Phenomena, DNA, Mitochondrial genetics, Energy Metabolism genetics, Mitochondrial Diseases genetics, Models, Genetic
- Abstract
The total amount of cellular mitochondrial DNA (mtDNA) varies widely and seems to be related to the nature and metabolic state of tissues and cells in culture. It is not known, however, whether this variation has any significance in vivo, and to which extent it regulates energy production. To better understand the importance of the cellular mtDNA level, we studied the influence of a gradual reduction of mtDNA copy number on oxidative phosphorylation in two models: (a) a control human cell line treated with different concentrations of 2', 3'-dideoxycytidine, a nucleoside analogue that inhibits mtDNA replication by interfering with mitochondrial DNA polymerase gamma, and (b) a cell line derived from a patient presenting mtDNA depletion. The two models were used to construct biochemical and phenotypic threshold curves. Our results show that oxidative phosphorylation activities are under a tight control by the amount of mtDNA in the cell, and that the full complement of mtDNA molecules are necessary to maintain a normal energy production level.
- Published
- 2008
- Full Text
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179. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma.
- Author
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Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, and Berger P
- Subjects
- Adult, Asthma metabolism, Cell Proliferation, DNA-Binding Proteins metabolism, Female, Heat-Shock Proteins metabolism, Humans, Male, Middle Aged, Mitochondrial Proteins metabolism, Models, Biological, Nuclear Respiratory Factor 1 metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive pathology, Transcription Factors metabolism, Asthma pathology, Bronchi metabolism, Calcium metabolism, Mitochondria metabolism, Muscle, Smooth metabolism
- Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling.
- Published
- 2007
- Full Text
- View/download PDF
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