Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjӧgren’s syndrome

Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress

“…Recently, mitochondrial RNAs (mtRNAs) have been receiving increasing attention as potent inducers of innate immunity [ 8 , 9 , 10 ]. Due to the bidirectional transcription of the circular genome, the mtDNA produces long complementary RNAs that can bind to each other to form intermolecular dsRNAs [ 11 ].…”

“…Due to the bidirectional transcription of the circular genome, the mtDNA produces long complementary RNAs that can bind to each other to form intermolecular dsRNAs [ 11 ]. When released to the cytosol, these mitochondrial dsRNAs (mt-dsRNAs) are recognized by MDA5 and protein kinase R (PKR) to trigger the type I IFN response and initiate apoptotic programs [ 8 , 9 , 10 , 12 ]. The cytosolic efflux of mt-dsRNAs occurs through the Bax/Bak pore either due to mutations in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene or by stressors that disturb the mitochondrial membrane potential [ 8 , 9 , 10 , 12 ].…”

“…When released to the cytosol, these mitochondrial dsRNAs (mt-dsRNAs) are recognized by MDA5 and protein kinase R (PKR) to trigger the type I IFN response and initiate apoptotic programs [ 8 , 9 , 10 , 12 ]. The cytosolic efflux of mt-dsRNAs occurs through the Bax/Bak pore either due to mutations in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene or by stressors that disturb the mitochondrial membrane potential [ 8 , 9 , 10 , 12 ]. Notably, recent studies reported a close association between the cytosolic release of mt-dsRNAs in the pathogenesis of human inflammatory diseases and aberrant immune activation.…”

“…Moreover, under osteoarthritis-eliciting conditions, such as mitochondrial dysfunction, increased levels of reactive oxygen species (ROS), and DNA damage, mt-dsRNAs are released to the cytosol, where they activate PKR to promote chondrocyte death [ 10 ]. Lastly, activation of antiviral signaling by exogenous dsRNAs also results in aberrant accumulation and the subsequent cytosolic release of mt-dsRNAs to promote downstream immune signaling pathways [ 9 ]. In this context, mt-dsRNAs act as positive feedback factors to potentiate the antiviral signaling initiated by the exogenous dsRNAs [ 9 ].…”

“…Lastly, activation of antiviral signaling by exogenous dsRNAs also results in aberrant accumulation and the subsequent cytosolic release of mt-dsRNAs to promote downstream immune signaling pathways [ 9 ]. In this context, mt-dsRNAs act as positive feedback factors to potentiate the antiviral signaling initiated by the exogenous dsRNAs [ 9 ].…”