Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS). This evidence concerns the gene SOD1 and amyotrophic lateral sclerosis.