Fiche publication
Date publication
octobre 2024
Journal
Brain : a journal of neurology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MONASSIER Laurent
Tous les auteurs :
Ropert B, Bannwarth S, Genin EC, Vaillant-Beuchot L, Lacas-Gervais S, Hounoum BM, Bernardin A, Dinh N, Mauri-Crouzet A, D'Elia MA, Augé G, Lespinasse F, Di Giorgio A, Meira W, Bonnefoy N, Monassier L, Schiff M, Sago L, Kilinc D, Brau F, Redeker V, Bohl D, Tribouillard-Tanvier D, Procaccio V, Azoulay S, Ricci JE, Delahodde A, Paquis-Flucklinger V
Lien Pubmed
Résumé
The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.
Mots clés
ALS, MICOS, mitochondrial disease, nifuroxazide
Référence
Brain. 2024 10 30;:
