Here we show in Caenorhabditis elegans models, cultured cells, primary neurons, and mouse brains that CHDHD10 normally plays a neuroprotective role and that FTD/ALS CHCHD10 mutations (R15L and S59L) display loss of function phenotypes and function in concert with TDP-43 to induce its cytoplasmic mislocalization, resulting in mitochondrial and synaptic damage. Here, CHCHD10 is linked to amyotrophic lateral sclerosis.