Figure 3.

VAPB-PTPIP51 binding regulates ER–mitochondria associations in response to Ca²⁺. In ALS: 1. TDP-43 reduces the amount of VAPB bound to PTPIP51; 2. TDP-43 produces Ca²⁺ dyshomeostasis following IP3R-mediated Ca²⁺ release from ER stores; 3. TDP-43 thus decreases ER–mitochondria associations. Ca²⁺ dyshomeostasis further results in reduced mitochondrial ATP production, impaired anterograde transport of mitochondria, and increased autophagy and ER stress. FUS interacts with VCP and alters VCP–vacuolar protein sorting-associated protein 13D (VPS13D) interactions at the MAM. Furthermore, TDP-43, SOD1, FUS, VAPB, and Sig-1R interact at the MAM to increase mitochondrial fission resulting in mitochondria with decreased membrane potential, and thus increase mitophagy.