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

Abstract

Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington’s disease, osteoarthritis, and autoimmune Sjögren’s syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response.

Mitochondrial Dysfunction in the Pathogenesis and Treatment of Oral Inflammatory Diseases

“…Direct suppression of mt-dsRNAs reversed the glandular phenotypes of SS [121]. The same group also demonstrated the therapeutic efficacy of muscarinic receptor ligand acetylcholine and resveratrol in reversing the activated response to immunogenic stressors in salivary gland acinar cells [122]. Xu et al confirmed that lactate levels were significantly upregulated in the salivary glands of patients with SS and lactate triggered an inflammatory response by damaging mtDNA and causing mtDNA leakage in glandular epithelial cells.…”

SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation

“…However, it remains unclear whether mtRNAs are always induced downstream of antiviral response or by other stressors. For example, mtRNAs were not induced under endoplasmic reticulum stress from increased misfolded proteins (Yoon et al 2023). Thus, we began our investigation by specifying stressors that can potentially modulate mtRNA expression.…”

“…mt-dsRNAs are generated due to bidirectional transcription of the mitochondrial circular genome 24,25 , which produces long complementary RNAs denoted as heavy and light strand RNAs 20,26–31 . Under stress conditions, mt-dsRNAs are released to the cytosol through BCL-2-associated X protein (BAX)/BCL-2- homologous antagonist/killer (BAK1) channel 28,32,33 where they activate MDA5 and PKR to initiate IFN response and apoptosis 28,34–36 . To limit mt-dsRNA expression, light strand mtRNAs are quickly degraded by mtRNA degradosome complex consisting of human suppressor of var1,3-like (hSUV3) 37 and polyribonucleotide nucleotidyltransferase 1 (PNPT1) 38–40 .…”