Our novel findings taken together therefore implicate the normal protective role of CHCHD10 in mitochondrial/synaptic integrity and inhibition of cytoplasmic TDP-43 accumulation, whereas the loss of CHCHD10 or FTD/ALS-associated CHCHD10 mutations (R15L and S59L) exhibit loss of function or dominant negative activities in these phenotypes. Here, TARDBP is linked to amyotrophic lateral sclerosis.