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

Authors :
Cittadini C
Germinario EAP
Maroccia Z
Cosentino L
Maselli V
Gambardella L
Giambenedetti M
Guidotti M
Travaglione S
Fallerini C
Renieri A
Marcillo DIE
Ricceri L
Fortini P
De Filippis B
Fiorentini C
Fabbri A
Source :
Journal of cellular and molecular medicine [J Cell Mol Med] 2023 May; Vol. 27 (10), pp. 1315-1326. Date of Electronic Publication: 2023 Apr 20.
Publication Year :
2023

Abstract

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.<br /> (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Details

Language :
English
ISSN :
1582-4934
Volume :
27
Issue :
10
Database :
MEDLINE
Journal :
Journal of cellular and molecular medicine
Publication Type :
Academic Journal
Accession number :
37078409
Full Text :
https://doi.org/10.1111/jcmm.17624