While most studies indicate that mitochondrial dysfunction occurs as a toxic gain of function, e.g., through poly(GR), C-terminal cleaved TDP-43, or TDP-43 aggregation, there is also evidence that loss of normal TDP-43 function can induce mitochondrial dysfunction These mechanisms are not exclusive and could converge to initiate the dysfunction observed in ALS motor neurons. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.