المؤلفون: Pelosi, Ludovic, Morbiato, Laura, Burgardt, Arthur, Tonello, Fiorella, Bartlett, Abigail, Guerra, Rachel, Ferizhendi, Katayoun Kazemzadeh, Desbats, Maria Andrea, Rascalou, Bérengère, Marchi, Marco, Vázquez-Fonseca, Luis, Agosto, Caterina, Zanotti, Giuseppe, Roger-Margueritat, Morgane, Alcázar-Fabra, María, García-Corzo, Laura, Sánchez-Cuesta, Ana, Navas, Plácido, Brea-Calvo, Gloria, Trevisson, Eva, Wendisch, Volker, Pagliarini, David, Salviati, Leonardo, Pierrel, Fabien

المساهمون: Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)

المصدر: ISSN: 1097-2765.

مصطلحات موضوعية: Coenzyme Q, Coenzyme Q biosynthesis, COQ4, Oxidative decarboxylation, mitochondria, respiratory chain, Coenzyme Q deficiency, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics andhomeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role, but also via oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis, and shed new light on thepathophysiology of human primary CoQ deficiency due to COQ4 mutations.

العلاقة: hal-04450030; https://hal.science/hal-04450030Test; https://hal.science/hal-04450030/documentTest; https://hal.science/hal-04450030/file/COQ4.pdfTest

الإتاحة: https://doi.org/10.1016/j.molcel.2024.01.003Test
https://hal.science/hal-04450030Test
https://hal.science/hal-04450030/documentTest
https://hal.science/hal-04450030/file/COQ4.pdfTest

المؤلفون: Colucci, Manuel, Zumerle, Sara, Bressan, Silvia, Gianfanti, Federico, Troiani, Martina, Valdata, Aurora, D’Ambrosio, Mariantonietta, Pasquini, Emiliano, Varesi, Angelica, Cogo, Francesca, Mosole, Simone, Dongilli, Cristina, Desbats, Maria Andrea, Contu, Liliana, Revankdar, Ajinkya, Chen, Jingjing, Kalathur, Madhuri, Perciato, Maria Luna, Basilotta, Rossella, Laczko, Endre, Schauer, Stefan, Othman, Alaa, id_orcid:0 000-0002-0092-5594

المصدر: Cancer Cell, 42 (4)

مصطلحات موضوعية: senescence, prostate cancer, SASP, immunotherapy, RAR, adapalene, AP-1, metabolism, NK-Killing, allogenic infusion

الوصف: Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in “immunologically cold” tumors. ; ISSN:1535-6108 ; ISSN:1878-3686

وصف الملف: application/application/pdf

العلاقة: http://hdl.handle.net/20.500.11850/668544Test

الإتاحة: https://doi.org/20.500.11850/668544Test
https://doi.org/10.3929/ethz-b-000668544Test
https://doi.org/10.1016/j.ccell.2024.02.004Test
https://hdl.handle.net/20.500.11850/668544Test

المؤلفون: Fonseca, Luis Vazquez, Doimo, Mara, Calderan, Cristina, Desbats, Maria Andrea, Acosta, Manuel J., Cerqua, Cristina, Cassina, Matteo, Ashraf, Shazia, Hildebrandt, Friedhelm, Sartori, Geppo, Navas, Placido, Trevisson, Eva, Salviati, Leonardo

المصدر: Human Mutation. 39(3):406-414

مصطلحات موضوعية: coenzyme Q deficiency, steroid-resistant nephrotic syndrome, yeast, COQ8B, mitochondrial phropathy

الوصف: Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a Delta COQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-145360Test
https://doi.org/10.1002/humu.23376Test
https://umu.diva-portal.org/smash/get/diva2:1190023/FULLTEXT01.pdfTest

المؤلفون: Sánchez-Rodríguez, Ricardo, Tezze, Caterina, Agnellini, Andrielly H. R., Angioni, Roberta, Venegas, Francisca C., Cioccarelli, Chiara, Munari, Fabio, Bertoldi, Nicole, Canton, Marcella, Desbats, Maria Andrea, Salviati, Leonardo, Gissi, Rosanna, Castegna, Alessandra, Soriano, Maria Eugenia, Sandri, Marco, Scorrano, Luca, Viola, Antonella, Molon, Barbara

المصدر: Cell Death & Differentiation ; volume 30, issue 3, page 742-752 ; ISSN 1350-9047 1476-5403

مصطلحات موضوعية: Cell Biology, Molecular Biology

الوصف: Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny. Optic atrophy 1 (OPA1) is a mitochondria-shaping protein controlling mitochondrial fusion, cristae biogenesis and respiration; clear evidence shows that the lack or dysfunctional activity of this protein triggers the accumulation of metabolic intermediates of the TCA cycle. In this study, we show that OPA1 has a crucial role in macrophage activation. Selective Opa1 deletion in myeloid cells impairs M1-macrophage commitment. Mechanistically, Opa1 deletion leads to TCA cycle metabolite accumulation and defective NF-κB signaling activation. In an in vivo model of muscle regeneration upon injury, Opa1 knockout macrophages persist within the damaged tissue, leading to excess collagen deposition and impairment in muscle regeneration. Collectively, our data indicate that OPA1 is a key metabolic driver of macrophage functions.

الإتاحة: https://doi.org/10.1038/s41418-022-01076-yTest
https://www.nature.com/articles/s41418-022-01076-y.pdfTest
https://www.nature.com/articles/s41418-022-01076-yTest

المؤلفون: Montioli, Riccardo, Sgaravizzi, Giada, Desbats, Maria Andrea, Grottelli, Silvia, Voltattorni, Carla Borri, Salviati, Leonardo, Cellini, Barbara

المساهمون: Montioli, Riccardo, Sgaravizzi, Giada, Desbats, Maria Andrea, Grottelli, Silvia, Voltattorni, Carla Borri, Salviati, Leonardo, Cellini, Barbara

مصطلحات موضوعية: gyrate atrophy, ornithine aminotransferase, pathogenic variant, pyridoxal phosphate, vitamin B6

الوصف: The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how each mutation leads to the deficit of OAT are mostly unknown. To fill this gap, we considered six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure. E. coli expression, spectroscopic, kinetic and bioinformatic analyses, reveal that the R154L and G237D mutations induce a catalytic more than a folding defect, the Q90E and R271K mutations mainly impact folding efficiency, while the E318K and C394Y mutations give rise to both folding and catalytic defects. In a human cellular model of disease folding-defective variants, although at a different extent, display reduced protein levels and/or specific activity, due to increased aggregation and/or degradation propensity. The supplementation with Vitamin B6, to mimic a treatment strategy available for GA patients, does not significantly improve the expression/activity of folding-defective variants, in contrast with the clinical responsiveness of patients bearing the E318K mutation. Thus, we speculate that the action of vitamin B6 could be also independent of hOAT. Overall, these data represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34395527; info:eu-repo/semantics/altIdentifier/wos/WOS:000685121900007; volume:8; issue:695205; firstpage:1; lastpage:13; numberofpages:13; journal:FRONTIERS IN MOLECULAR BIOSCIENCES; http://hdl.handle.net/11562/1047384Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85112443465; https://doi.org/10.3389/fmolb.2021.695205Test

الإتاحة: https://doi.org/10.3389/fmolb.2021.695205Test
http://hdl.handle.net/11562/1047384Test

المؤلفون: Desbats, Maria Andrea, Zumerle, Sara, Alimonti, Andrea

المساهمون: Associazione Italiana per la Ricerca sul Cancro

المصدر: Nature Aging ; volume 1, issue 5, page 420-421 ; ISSN 2662-8465

مصطلحات موضوعية: Neuroscience (miscellaneous), Geriatrics and Gerontology, Aging

الإتاحة: https://doi.org/10.1038/s43587-021-00068-wTest
https://www.nature.com/articles/s43587-021-00068-w.pdfTest
https://www.nature.com/articles/s43587-021-00068-wTest

المؤلفون: Giacomini, Isabella, Gianfanti, Federico, Desbats, Maria Andrea, Orso, Genny, Berretta, Massimiliano, Prayer-Galetti, Tommaso, Ragazzi, Eugenio, Cocetta, Veronica

المساهمون: Università degli Studi di Padova

المصدر: Frontiers in Oncology ; volume 11 ; ISSN 2234-943X

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

الإتاحة: https://doi.org/10.3389/fonc.2021.682911Test

المؤلفون: Desbats, Maria Andrea, Salviati, Leonardo

المساهمون: Desbats, Maria Andrea, Salviati, Leonardo

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37671546; info:eu-repo/semantics/altIdentifier/wos/WOS:001067803500001; volume:146; issue:10; firstpage:3958; lastpage:3959; numberofpages:2; journal:BRAIN; https://hdl.handle.net/11577/3506265Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85174080216

الإتاحة: https://doi.org/10.1093/brain/awad302Test
https://hdl.handle.net/11577/3506265Test

المؤلفون: Desbats, Maria Andrea, Giacomini, Isabella, Prayer-Galetti, Tommaso, Montopoli, Monica

المصدر: Frontiers in Oncology ; volume 10 ; ISSN 2234-943X

الإتاحة: https://doi.org/10.3389/fonc.2020.00281Test

المؤلفون: Calderan, Cristina, Sorrentino, Ugo, Persano, Luca, Trevisson, Eva, Sartori, Geppo, Salviati, Leonardo, Desbats, Maria Andrea

المصدر: European Journal of Human Genetics: EJHG; 20240101, Issue: Preprints p1-9, 9p

مستخلص: The ACTA2gene codes for alpha-smooth muscle actin, a critical component of the contractile apparatus of the vascular smooth muscle cells. Autosomal dominant variants in the ACTA2gene have been associated to familial non-syndromic thoracic aortic aneurysm/dissection (TAAD). They are thought to act through a dominant-negative mechanism. These variants display incomplete penetrance and variable expressivity, complicating the validation of ACTA2variants pathogenicity by family segregation studies. In this study, we developed a yeast based assay to test putative TAAD-associated ACTA2variants. We identified five new heterozygous ACTA2missense variants in TAAD patients through next generation sequencing. We decided to test their pathogenicity in Saccharomyces cerevisiae, since yeast actin is very similar to human alpha-smooth muscle actin, and the residues at which the TAAD-associated variants occur in ACTA2 are well conserved. A wild type yeast strain was transformed with a vector expressing the different mutant alleles, to model the heterozygous condition of patients. Then, we evaluated yeast growth by spot test and cytoskeletal and mitochondrial morphology by fluorescence microscopy. We found that mutant yeast strains displayed only mild growth defects but a significant increase in the percentage of cells with abnormal mitochondrial distribution and abnormal organization of the actin cytoskeleton compared to controls. All variants appeared to interfere with the activity of wild type actin in yeast, suggesting a dominant-negative pathogenic mechanism. Our results demonstrate the utility of using the yeast actin model system to validate the pathogenicity of TAAD-associated ACTA2variants.