Herein, we present the first in vivo evidence that the FTD/ALS-linked CHCHD10R15L and CHCHD10S59L mutations drive CHCHD10 and TDP-43 proteinopathies originating from mitochondria, which directly mirror the functional changes in long-term synaptic plasticity and motor unit physiology. This evidence concerns the gene CHCHD10 and amyotrophic lateral sclerosis.