Figure 3.

MERCS in health and in ALS/FTD. In healthy controls (upper part of the figure), different functions of MERCS are integrated to maintain cell homeostasis. Complex IP3Rs-Grp75-VDAC1 and VAPB-PTPIP51 modulate the ultrastructure of MERCS. In ALS/FTD, FUS and TDP43 activate GSK-3β, which dissociates PTPIP51 and VAPB and decreases the connectivity between the ER and mitochondria. Mutation in Sigma-1R (mSig1R) leads to the accumulation of these proteins at MERCS and to mislocalization of IP3R outside MERCS, leading to a juvenile form of ALS. Mutation in VAPB (mVAPB) leads to an increase in MERCS and an increase in the flow of Ca²⁺ inside mitochondria. Different colours correspond to proteins involved in different cellular processes and faded colours as well as dashed lines represent the downregulation of the process or protein level/function.