Fig. 2.

STAT3 canonical and non-canonical pathways. In SAFE pathway JAK/STAT3 can be activated upon activation of receptors including gp130, TNFR2, S1PR. Other molecules (not represented in figure) may activate SAFE pathway, including HDL, Melatonin, Erythropoietin, Insulin and Leptin. Upon phosphorylation at Y705 and dimerization, STAT3 dimer travels to the nucleus, where it regulates gene transcription. The phosphorylation at S727 may allow STAT3 to interact with GRIM19 and TOM20 to enter the mitochondria. STAT3 has been shown to interact with multiple mitochondrial proteins, such as MCU, promoting mitochondrial Ca²⁺ entry, complex I and II of the ETC, increasing ATP level and decreasing ROS production. STAT3 interacting with CypD prevents the opening of mPTPs. STAT3 has been detected also in the MAM fraction, where it is able to promote IPR3 degradation and prevent cytosolic Ca²⁺ accumulation. Akt Protein kinase B, ATP adenosine triphosphate, Bcl-xL B-cell lymphoma-extra large, COX2 Cytochrome c oxidase subunit 2, CypD Cyclophilin D, Cyt C Cytochrome C, ER Endoplasmic Reticulum, ERK1/2 Extracellular Receptor Kinase ½, ETC Electron Transport Chain, gp130 glycoprotein 130, GRIM19 Gene associated with Retinoid Interferon-induced cell Mortality 19, HDL High Density Lipoprotein; IP3R, Inositol 1,4,5-trisphosphate Receptors, JAK Janus Kinase, MAM Mitochondrial-Associated ER Membrane, MCl-1 Myeloid cell leukemia 1, MCU Mitochondrial Calcium Uniporter, mPTP mitochondrial Permeability Transition Pore, ROS Reactive oxygen species, S1P Sphingosine-1-Phosphate, S1PR Sphingosine-1-Phosphate Receptors, SAFE Survivor Activating Factor Enhancement, SERCA Sarco-Endoplasmic Reticulum Calcium ATPase, SK1 Sphingosine Kinase 1, SOCS3 Suppressor of Cytokine Signaling 3; SOD2 Superoxide dismutase 2, STAT3 Signal Transducer and Activator of Transcription 3, TNFR2 Tumor Necrosis Factor Receptor 2; TOM20Translocase of the outer membrane 20, TRAF2 TNF-Receptor-Associated-Factor 2, VDAC Voltage-Dependent Anion Channels, VEGF Vascular endothelial growth factor