The V57E pathological variant of the mitochondrial coiled-coil-helix-coiled-coil-helixdomain-containing protein 10 (CHCHD10) plays a role in frontotemporaldementia. The wild-type and V57E mutant CHCHD10 proteins contain intrinsicallydisordered regions, and therefore, these regions hampered structuralcharacterization of these proteins using conventional experimentaltools. For the first time in the literature, we represent that theV57E mutation is pathogenic to mitochondria as it increases mitochondrialsuperoxide and impairs mitochondrial respiration. In addition, werepresent here the structural ensemble properties of the V57E mutantCHCHD10 and describe the impacts of V57E mutation on the structuralensembles of wild-type CHCHD10 in aqueous solution. We conducted experimentaland computational studies for this research. Namely, MitoSOX Red stainingand Seahorse Mito Stress experiments, atomic force microscopy measurements,bioinformatics, homology modeling, and multiple-run molecular dynamicssimulation computational studies were conducted. Our experiments showthat the V57E mutation results in mitochondrial dysfunction, and ourcomputational studies present that the structural ensemble propertiesof wild-type CHCHD10 are impacted by the frontotemporal dementia-associatedV57E genetic mutation.