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Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study

The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanis...

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Autores principales: Cittadini, Camilla, Germinario, Elena Angela Pia, Maroccia, Zaira, Cosentino, Livia, Maselli, Valeria, Gambardella, Lucrezia, Giambenedetti, Massimo, Guidotti, Marco, Travaglione, Sara, Fallerini, Chiara, Renieri, Alessandra, Marcillo, David Israel Escobar, Ricceri, Laura, Fortini, Paola, De Filippis, Bianca, Fiorentini, Carla, Fabbri, Alessia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183712/
https://www.ncbi.nlm.nih.gov/pubmed/37078409
http://dx.doi.org/10.1111/jcmm.17624
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author Cittadini, Camilla
Germinario, Elena Angela Pia
Maroccia, Zaira
Cosentino, Livia
Maselli, Valeria
Gambardella, Lucrezia
Giambenedetti, Massimo
Guidotti, Marco
Travaglione, Sara
Fallerini, Chiara
Renieri, Alessandra
Marcillo, David Israel Escobar
Ricceri, Laura
Fortini, Paola
De Filippis, Bianca
Fiorentini, Carla
Fabbri, Alessia
author_facet Cittadini, Camilla
Germinario, Elena Angela Pia
Maroccia, Zaira
Cosentino, Livia
Maselli, Valeria
Gambardella, Lucrezia
Giambenedetti, Massimo
Guidotti, Marco
Travaglione, Sara
Fallerini, Chiara
Renieri, Alessandra
Marcillo, David Israel Escobar
Ricceri, Laura
Fortini, Paola
De Filippis, Bianca
Fiorentini, Carla
Fabbri, Alessia
author_sort Cittadini, Camilla
collection PubMed
description The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease‐in‐a‐dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1‐induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re‐organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT.
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spelling pubmed-101837122023-05-16 Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study Cittadini, Camilla Germinario, Elena Angela Pia Maroccia, Zaira Cosentino, Livia Maselli, Valeria Gambardella, Lucrezia Giambenedetti, Massimo Guidotti, Marco Travaglione, Sara Fallerini, Chiara Renieri, Alessandra Marcillo, David Israel Escobar Ricceri, Laura Fortini, Paola De Filippis, Bianca Fiorentini, Carla Fabbri, Alessia J Cell Mol Med Original Articles The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease‐in‐a‐dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1‐induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re‐organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT. John Wiley and Sons Inc. 2023-04-20 /pmc/articles/PMC10183712/ /pubmed/37078409 http://dx.doi.org/10.1111/jcmm.17624 Text en © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Cittadini, Camilla
Germinario, Elena Angela Pia
Maroccia, Zaira
Cosentino, Livia
Maselli, Valeria
Gambardella, Lucrezia
Giambenedetti, Massimo
Guidotti, Marco
Travaglione, Sara
Fallerini, Chiara
Renieri, Alessandra
Marcillo, David Israel Escobar
Ricceri, Laura
Fortini, Paola
De Filippis, Bianca
Fiorentini, Carla
Fabbri, Alessia
Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title_full Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title_fullStr Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title_full_unstemmed Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title_short Effects of the Rho GTPase‐activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study
title_sort effects of the rho gtpase‐activating toxin cnf1 on fibroblasts derived from rett syndrome patients: a pilot study
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10183712/
https://www.ncbi.nlm.nih.gov/pubmed/37078409
http://dx.doi.org/10.1111/jcmm.17624
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