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. The gene discussed is TARDBP; the disease is frontotemporal dementia.