المؤلفون: Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N. Feige, Umberto De Marchi

المصدر: Redox Biology, Vol 64, Iss , Pp 102759- (2023)

مصطلحات موضوعية: Mitochondria, Calcium signaling, Redox biology, Skeletal muscle, MCU, C. elegans, Medicine (General), R5-920, Biology (General), QH301-705.5

الوصف: Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S221323172300160X; https://doaj.org/toc/2213-2317

URL الوصول: https://doaj.org/article/a579efc55ff94776a164adcc0e5fb71f

المؤلفون: Nadège Zanou, Haikel Dridi, Steven Reiken, Tanes Imamura de Lima, Chris Donnelly, Umberto De Marchi, Manuele Ferrini, Jeremy Vidal, Leah Sittenfeld, Jerome N. Feige, Pablo M. Garcia-Roves, Isabel C. Lopez-Mejia, Andrew R. Marks, Johan Auwerx, Bengt Kayser, Nicolas Place

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021)

مصطلحات موضوعية: Science

الوصف: Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/74a4add40ec849d4a47b99015d48a534

المؤلفون: Corinne Haller, Julie Piccand, Filippo De Franceschi, Yuki Ohi, Anindita Bhoumik, Christophe Boss, Umberto De Marchi, Guillaume Jacot, Sylviane Metairon, Patrick Descombes, Andreas Wiederkehr, Alessio Palini, Nicolas Bouche, Pascal Steiner, Olivia G. Kelly, Marine R.-C. Kraus

المصدر: Stem Cell Reports, Vol 12, Iss 4, Pp 787-800 (2019)

مصطلحات موضوعية: Medicine (General), R5-920, Biology (General), QH301-705.5

الوصف: Summary: In type 1 diabetes, a renewable source of human pancreatic β cells, in particular from human induced pluripotent stem cell (hiPSC) origin, would greatly benefit cell therapy. Earlier work showed that pancreatic progenitors differentiated from human embryonic stem cells in vitro can further mature to become glucose responsive following macroencapsulation and transplantation in mice. Here we took a similar approach optimizing the generation of pancreatic progenitors from hiPSCs. This work demonstrates that hiPSCs differentiated to pancreatic endoderm in vitro can be efficiently and robustly generated under large-scale conditions. The hiPSC-derived pancreatic endoderm cells (HiPECs) can further differentiate into glucose-responsive islet-like cells following macroencapsulation and in vivo implantation. The HiPECs can protect mice from streptozotocin-induced hyperglycemia and maintain normal glucose homeostasis and equilibrated plasma glucose concentrations at levels similar to the human set point. These results further validate the potential use of hiPSC-derived islet cells for application in clinical settings. : In this article, Kraus and colleagues show that human induced pluripotent stem cells can robustly and efficiently be differentiated to pancreatic endoderm in a large-scale setup. Moreover, after macroencapsulation and further in vivo maturation, hiPSC-derived pancreatic endoderm cells can give rise to glucose-responsive β cells, which protect mice from STZ-induced hyperglycemia. Keywords: β cell, diabetes mellitus, differentiation, human, stem cell, iPSC, encapsulation, therapy

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2213671119300505; https://doaj.org/toc/2213-6711

URL الوصول: https://doaj.org/article/3f66809f796c41b7b0c7c165f61695af

المؤلفون: Jaime Santo-Domingo, Antonio Núñez Galindo, Ornella Cominetti, Umberto De Marchi, Pedro Cutillas, Loïc Dayon, Andreas Wiederkehr

المصدر: Cell Communication and Signaling, Vol 17, Iss 1, Pp 1-19 (2019)

مصطلحات موضوعية: Glucose, Mass spectrometry, Metabolism, Mitochondria, Signaling, Phospho-proteome, Medicine, Cytology, QH573-671

الوصف: Abstract Background Glucose is the main secretagogue of pancreatic beta-cells. Uptake and metabolism of the nutrient stimulates the beta-cell to release the blood glucose lowering hormone insulin. This metabolic activation is associated with a pronounced increase in mitochondrial respiration. Glucose stimulation also initiates a number of signal transduction pathways for the coordinated regulation of multiple biological processes required for insulin secretion. Methods Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on lysates from glucose-stimulated INS-1E cells was used to identify glucose regulated phosphorylated proteins and signal transduction pathways. Kinase substrate enrichment analysis (KSEA) was applied to identify key regulated kinases and phosphatases. Glucose-induced oxygen consumption was measured using a XF96 Seahorse instrument to reveal cross talk between glucose-regulated kinases and mitochondrial activation. Results Our kinetic analysis of substrate phosphorylation reveal the molecular mechanism leading to rapid activation of insulin biogenesis, vesicle trafficking, insulin granule exocytosis and cytoskeleton remodeling. Kinase-substrate enrichment identified upstream kinases and phosphatases and time-dependent activity changes during glucose stimulation. Activity trajectories of well-known glucose-regulated kinases and phosphatases are described. In addition, we predict activity changes in a number of kinases including NUAK1, not or only poorly studied in the context of the pancreatic beta-cell. Furthermore, we pharmacologically tested whether signaling pathways predicted by kinase-substrate enrichment analysis affected glucose-dependent acceleration of mitochondrial respiration. We find that phosphoinositide 3-kinase, Ca2+/calmodulin dependent protein kinase and protein kinase C contribute to short-term regulation of energy metabolism. Conclusions Our results provide a global view into the regulation of kinases and phosphatases in insulin secreting cells and suggest cross talk between glucose-induced signal transduction and mitochondrial activation.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s12964-019-0326-6; https://doaj.org/toc/1478-811X

URL الوصول: https://doaj.org/article/630414b375bd4c67a6b87d4f1b051dc9

المؤلفون: Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N. Feige, Cristina Mammucari, Umberto De Marchi

الوصف: SUMMARYMitochondrial calcium (mtCa2+) uptake via the Mitochondrial Calcium Uniporter (MCU) couples the regulation of calcium homeostasis to energy production. mtCa2+uptake is rate-limiting for mitochondrial activation during muscle contraction, but how MCU is affected during physiopathology and whether it can be stimulated therapeutically remains largely uncharacterized. By profiling human and preclinical aging of skeletal muscle, we discovered a conserved down-regulation of MCUR1 during aging that decreases mtCa2+uptake and drives sarcopenia. Through a screen of 5000 bioactive nutrients, we identify the natural polyphenol Oleuropein as a specific MCU activator that stimulates mitochondrial respiration via binding to MICU1. Oleuropein activates mtCa2+uptake and oxidative energy metabolism to enhance endurance and limit fatigue in vivo both in young and aged. These effects of Oleuropein are mediated by an MCU-dependent mechanism in skeletal muscle as they are lost upon muscle-specific MCU KO. Our work demonstrates that impaired mtCa2+uptake causes mitochondrial dysfunction during aging and establishes Oleuropein as a novel nutrient that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::1a196ae356497202c5b69aa3aac44bdb
https://doi.org/10.1101/2023.02.24.529830

المؤلفون: Anna Weiser, Jerome N. Feige, Umberto De Marchi

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 5, p 2515 (2021)

مصطلحات موضوعية: mitochondria, calcium, insulin secretion, β-cell, diabetes, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Accumulation of calcium in energized mitochondria of pancreatic β-cells is emerging as a crucial process for pancreatic β-cell function. β-cell mitochondria sense and shape calcium signals, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion during nutrient stimulation. Here, we describe the role of mitochondrial calcium signaling in pancreatic β-cell function. We report the latest pharmacological and genetic findings, including the first mitochondrial calcium-targeted intervention strategies developed to modulate pancreatic β-cell function and their potential relevance in the context of diabetes.

وصف الملف: electronic resource

Relation: https://www.mdpi.com/1422-0067/22/5/2515; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067

URL الوصول: https://doaj.org/article/a936bed54fa64cf0be5b2c0d11538a59

المؤلفون: Julien Marquis, Gregory Lefebvre, Yiannis A. I. Kourmpetis, Mohamed Kassam, Frédéric Ronga, Umberto De Marchi, Andreas Wiederkehr, Patrick Descombes

المصدر: BMC Genomics, Vol 18, Iss 1, Pp 1-19 (2017)

مصطلحات موضوعية: Next generation sequencing, Mitochondria, Mitochondrial DNA, Heteroplasmy, Rolling circle amplification, Somatic mutation, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background Mitochondrial dysfunction is linked to numerous pathological states, in particular related to metabolism, brain health and ageing. Nuclear encoded gene polymorphisms implicated in mitochondrial functions can be analyzed in the context of classical genome wide association studies. By contrast, mitochondrial DNA (mtDNA) variants are more challenging to identify and analyze for several reasons. First, contrary to the diploid nuclear genome, each cell carries several hundred copies of the circular mitochondrial genome. Mutations can therefore be present in only a subset of the mtDNA molecules, resulting in a heterogeneous pool of mtDNA, a situation referred to as heteroplasmy. Consequently, detection and quantification of variants requires extremely accurate tools, especially when this proportion is small. Additionally, the mitochondrial genome has pseudogenized into numerous copies within the nuclear genome over the course of evolution. These nuclear pseudogenes, named NUMTs, must be distinguished from genuine mtDNA sequences and excluded from the analysis. Results Here we describe a novel method, named MitoRS, in which the entire mitochondrial genome is amplified in a single reaction using rolling circle amplification. This approach is easier to setup and of higher throughput when compared to classical PCR amplification. Sequencing libraries are generated at high throughput exploiting a tagmentation-based method. Fine-tuned parameters are finally applied in the analysis to allow detection of variants even of low frequency heteroplasmy. The method was thoroughly benchmarked in a set of experiments designed to demonstrate its robustness, accuracy and sensitivity. The MitoRS method requires 5 ng total DNA as starting material. More than 96 samples can be processed in less than a day of laboratory work and sequenced in a single lane of an Illumina HiSeq flow cell. The lower limit for accurate quantification of single nucleotide variants has been measured at 1% frequency. Conclusions The MitoRS method enables the robust, accurate, and sensitive analysis of a large number of samples. Because it is cost effective and simple to setup, we anticipate this method will promote the analysis of mtDNA variants in large cohorts, and may help assessing the impact of mtDNA heteroplasmy on metabolic health, brain function, cancer progression, or ageing.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s12864-017-3695-5; https://doaj.org/toc/1471-2164

URL الوصول: https://doaj.org/article/adfb5723054345a9a8bebe8591d45b4b

المؤلفون: Sergio, De Marchi, Emanuela, Cecchin, Sergio Umberto, De Marchi, Federico, Iuri, Leonardo A, Sechi

مصطلحات موضوعية: Atopy patch test, Allergic conjunctivitis, Allergic rhinitis, Asthma, Chronic rhinosinusitis with nasal polyps, Dermatophagoides, Endotypes, Immunology and Allergy

الوصف: The impact of delayed hypersensitivity to dermatophagoides pteronyssinus (DP) on comorbidities of allergic rhinitis (AR) is unknown.The primary endpoint was to test the hypothesis that DP-induced AR could be divided into two subendotypes based on the presence or absence of a delayed type mite sensitization detected by the positive atopy patch test (DP-APT). The second endpoint was to evaluate differences in the long-term risk of respiratory comorbidities and nasal airway response to mite exposure.In a prospective observational study we included 472 patients with DP-induced AR. 343 patients had positive results of skin prick test /serum specific IgE and DP-APT and were assigned to a subendotype with both IgE and T cell-mediated mite sensitization (BMSS). The remaining 129 patients without delayed type mite sensitization were included in the subendotype with only IgE-mediated mite sensitization (SMSS). Nasal allergen provocation test with active anterior rhinomanometry, paranasal sinuses CT scan, nasal endoscopy, and spirometry were performed.At baseline BMSS showed a longer increase of nasal airway resistance, total nasal score and visual analogue scale to mite exposure. During a 15-year follow-up, 56 patients developed chronic rhinosinusitis with nasal polyps (CRSwNP) with higher incidence in BMSS than in SMSS (50 patients, 14.6% vs 6 patients, 12.4%; P0.001). BMSS also showed a higher incidence of conjunctivitis (25.7% vs 12.4%; P0.01). The rate of adult-onset asthma did not differ between groups but patients with BMSS showed a more frequent link to CRSwNP (6 of 29 patients, 20.7% vs 0 of 10 patients, 0%). DP-APT independently predicted CRSwNP and conjunctivitis.Two subendotypes with significantly different clinical outcome can be identified among patients with DP-induced AR according to the presence of delayed type mite sensitization detected by positive DP-APT.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::26126fe3e356603cf01af4f11e48fc38
https://hdl.handle.net/11390/1241529

المؤلفون: Flavien Bermont, Aurelie Hermant, Romy Benninga, Christian Chabert, Guillaume Jacot, Jaime Santo-Domingo, Marine R-C Kraus, Jerome N. Feige, Umberto De Marchi

المصدر: Nutrients, Vol 12, Iss 2, p 538 (2020)

مصطلحات موضوعية: mitochondria, calcium, insulin, polyphenols, β-cell, kaempferol, mitoxantrone, Nutrition. Foods and food supply, TX341-641

الوصف: Pancreatic β-cells secrete insulin to lower blood glucose, following a meal. Maintenance of β-cell function is essential to preventing type 2 diabetes. In pancreatic β-cells, mitochondrial matrix calcium is an activating signal for insulin secretion. Recently, the molecular identity of the mitochondrial calcium uniporter (MCU), the transporter that mediates mitochondrial calcium uptake, was revealed. Its role in pancreatic β-cell signal transduction modulation was clarified, opening new perspectives for intervention. Here, we investigated the effects of a mitochondrial Ca2+-targeted nutritional intervention strategy on metabolism/secretion coupling, in a model of pancreatic insulin-secreting cells (INS-1E). Acute treatment of INS-1E cells with the natural plant flavonoid and MCU activator kaempferol, at a low micromolar range, increased mitochondrial calcium rise during glucose stimulation, without affecting the expression level of the MCU and with no cytotoxicity. Enhanced mitochondrial calcium rises potentiated glucose-induced insulin secretion. Conversely, the MCU inhibitor mitoxantrone inhibited mitochondrial Ca2+ uptake and prevented both glucose-induced insulin secretion and kaempferol-potentiated effects. The kaempferol-dependent potentiation of insulin secretion was finally validated in a model of a standardized pancreatic human islet. We conclude that the plant product kaempferol activates metabolism/secretion coupling in insulin-secreting cells by modulating mitochondrial calcium uptake.

وصف الملف: electronic resource

Relation: https://www.mdpi.com/2072-6643/12/2/538; https://doaj.org/toc/2072-6643

URL الوصول: https://doaj.org/article/ddf5df6eb7f641139d697459af1acb61

المؤلفون: Julien B. Pujol, Eija Heikkila, Claudia Savoia, Asghar Hajibeigi, Umberto De Marchi, Pavan K. Battiprolu, Orhan K. Öz, El Hadji M. Dioum

المصدر: International Journal of Molecular Sciences, Vol 19, Iss 9, p 2542 (2018)

مصطلحات موضوعية: Isx9, apoptosis, calbindin-D28K, calcium homeostasis, inflammation, serum deprivation, calcineurin, NFAT transcription factor, β cell function, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Pancreatic β-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of β-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for β-cell function and improves glycemia in a model of β cell regeneration. We further investigated the role of Isx9 in β-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in β cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected β cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.

وصف الملف: electronic resource

Relation: http://www.mdpi.com/1422-0067/19/9/2542; https://doaj.org/toc/1422-0067

URL الوصول: https://doaj.org/article/2eaa9581ba794423835c25256ad5ddb0