We here show that the initiation of ER-stress-induced compensatory responses involve the enhanced expression of glucose-regulated protein 75 (GRP75) at mitochondria-associated membranes (MAMs), counteracting early mitochondrial Ca2+ imbalance in human C9ORF72-ALS/FTD and C9orf72 mouse neurons. This evidence concerns the gene C9orf72 and amyotrophic lateral sclerosis.