Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

Figure 2

Ca²⁺ transfer between the ER and mitochondria under normal and ER stress conditions. Direct Ca²⁺ transfer from the ER lumen into the mitochondria occurs at contact sites that are maintained by Mfn2 on the ER and Mfn1 or Mfn2 on mitochondria and is facilitated by the IP₃R/GRP75/VDAC complex that also involves the mitochondrial calcium uniporter (MCU) on the outer mitochondrial membrane (IMM). The amount of Ca²⁺ released through the IP₃R that can be transmitted to mitochondria, which can be controlled by the ER chaperone Sig1R, determines cell fate. In normal conditions Ca²⁺ released from the ER to mitochondria triggers cellular metabolism and ATP production. However, mitochondrial Ca²⁺ overload induced by ER stress sensitizes mitochondria to generate ROS and to release apoptotic factors.