Frontotemporal Dementia-Related V57E Mutation Impairs Mitochondrial Function and Alters the Structural Properties of...

The V57E pathological variant of the mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) plays a role in frontotemporal dementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsically disordered regions, and therefore, these regions hampered structural characterization of these proteins using conventional experimental tools. For the first time in the literature, we represent that the V57E mutation is pathogenic to mitochondria as it increases mitochondrial superoxide and impairs mitochondrial respiration. In addition, we represent here the structural ensemble properties of the V57E mutant CHCHD10 and describe the impacts of V57E mutation on the structural ensembles of wild-type CHCHD10 in aqueous solution. We conducted experimental and computational studies for this research. Namely, MitoSOX Red staining and Seahorse Mito Stress experiments, atomic force microscopy measurements, bioinformatics, homology modeling, and multiple-run molecular dynamics simulation computational studies were conducted. Our experiments show that the V57E mutation results in mitochondrial dysfunction, and our computational studies present that the structural ensemble properties of wild-type CHCHD10 are impacted by the frontotemporal dementia-associated V57E genetic mutation.