MitoCOSMIC

The identification of a point mutation (p.S59L) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Indeed CHCHD10-associated variants are responsible for mitochondrial myopathy and cardiomyopathy but also for amyotrophic lateral sclerosis (ALS ) and frontotemporal dementia (FTD.) We have shown that the p.S59L variant leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Our results suggest that a mitochondrial transport defect along axons may be involved in our model in connection with the disorganization of MICOS. We identified nifuroxazide (NFX), as a broad-spectrum antibacterial molecule, able to rescue the growth defect of yeast mutant strains mimicking MICOS instability. NFX rescues mitochondrial network fragmentation and cristae abnormalities found in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human motor neurons derived from iPSCs carrying the p.S59L variant. The positive effects of NFX on mitochondrial settings in CHCHD10S59L/+ cells seem to depend on KIF5B, a protein involved in mitochondrial transport. Our project aims (1) to analyze mitochondrial trafficking and understand the link with cristae disorganization via NFX mechanism of action and (2) to characterize interactions between MICOS, transport machinery and mitophagy. We generated a KI Chchd10S59L/+ mouse that recapitulates all clinical phenotypes found in the patients. As our results identify NFX and selected structural analogues as potential therapeutic molecules for disorders associated with MICOS disassembly, we aim (3) to carry out a preclinical study on these mice to determine whether NFX may have a therapeutic effect in vivo. Last, we want (4) to investigate whether the dysfunctions identified in our models also occur in ALS of other origins.