Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.

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 two 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/+ induced pluripotent stem cell-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.