Figure 4.

The cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon genes (STING) pathway is activated during cardiorenal syndrome type 4. In chronic kidney disease (CKD), reactive oxygen species (ROS) and other factors cause the release of mitochondrial deoxyribonucleic acid (DNA) fragments that might travel to the cardiomyocytes of the heart. Mitochondrial DNA (mtDNA) or foreign DNA enters the cell and activates cGAS, beginning the signaling cascade. In addition, external perturbations cause damage to cardiac mitochondria, inducing the opening of the mitochondrial outer membrane (MOM) via the pro-apoptotic B-cell lymphoma proteins B-cell lymphoma 2 (BCL-2)-associated X (Bax) and promoting the release of mtDNA. The latter activates cGAS. cGAS activation forms the product 2′3′cyclic GMP-AMP, which induces cyclic GMP-AMP binding to the STING protein in the endoplasmic reticulum (ER) membrane. Then, STING translocates from ER to Golgi, forming a complex with the Tumor necrosis factor receptor (TNFR)-associated factors (TRAF) family member associated NF-κB activator (TANK)-binding kinase (TBK1), delivering TBK1 to endolysosomes. TBK1 phosphorylates the interferon regulatory (IRF3) and nuclear factor-kappa B (NF-κB) in endolysosomes, promoting their translocation to the nucleus to induce the transcription of type I interferon (IFN) and inflammatory cytokines and chemokines, respectively. Finally, c-GAS and STING are degraded via autophagy. ΔΨ: mitochondrial membrane potential. Figure created by using Biorender.com.