ALS/FTD-associated FUS activates GSK-3[beta] to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations

Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3[beta] (GSK-3[beta]), a kinase already strongly associated with ALS/FTD. Synopsis This study shows that FUS, by disrupting ER and mitochondria associations, regulates calcium uptake into and ATP production by mitochondria, with implications for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). FTD/ALS-associated fused in sarcoma (FUS) disrupts ER-mitochondria associations and links calcium homoeostasis and mitochondrial ATP production. FUS-induced disruption of ER-mitochondria associations involves activation of GSK-3[beta] and breaking of the VAPB-PTPIP51 ER-mitochondria tethering proteins.