Fig. 5

Representation of intracellular Ca²⁺ dynamics and MAM proteins involved in ER–mitochondria Ca²⁺ crosstalk in patients with NAFLD. A range of proteins (e.g., PML, Akt, GRP-75, SIG-1R, Mfn1/2, and BiP) located in MAMs regulate Ca²⁺ release from the ER and efficient mitochondrial Ca²⁺ uptake, resulting in different consequences. FFAs stimulate the ER in patients with NAFLD, thereby promoting the transport of Ca²⁺ ions from the ER to MAMs or the cytoplasm by IP3R. The formation of locally high Ca²⁺ concentration microdomains drives Ca²⁺ into the mitochondrial matrix through VDAC and MCU, and ER Ca²⁺ transfer is enhanced by GRP75. Increases in mitochondrial Ca²⁺ concentrations promote the production of NADH by enzymes in the TCA cycle and increase ATP synthesis and ROS production. Sustained increases in Ca²⁺ concentrations promote mPTP opening followed by the release of cytochrome c (cyt c) and the induction of apoptosis. In addition, PERK may promote the rapid transfer of ROS signals to MAMs in the form of lipid hydroperoxides. As a result, mitochondrial phospholipids are oxidized, and cyt c is released from the mitochondrial pool in close contact with the ER. Interestingly, after transmission of the apoptotic signal, the BH3 family member Bik induces Ca²⁺ release from the ER, which in turn induces the recruitment of Drp1 to the mitochondria. Reductions in ER Ca²⁺ ion concentrations increase the production of unfolded proteins or misfolded proteins, leading to ERS and ROS production. ROS or their signals cause further disturbances in Ca²⁺ homeostasis, creating a vicious positive feedback cycle