MitoCOSMIC: Loss of mitochondrial cristae structure in motor neuron disease: mechanistic and therapeutic approaches. 2025-2027, ANR
Our results suggest that a mitochondrial transport defect along axons may be involved in CHCHD10-associated neuronal degeneration, in connection with the disorganization of MICOS. 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, and transport machinery. 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.