Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology

Abstract

Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.

LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus

“…Binding of viral RNA to RLRs induces a conformational change, allowing their recruitment to the mitochondrial RLR adaptor protein MAVS (mitochondrial antiviral signaling protein). Subsequent multimerization of MAVS at mitochondria results in the activation of the transcription factors and IRF (interferonregulatory factor) 3, IRF7, and NF-ĸB (nuclear factor kappa B) that regulate the expression of type 1 interferons and pro-inflammatory cytokines (Ablasser and Hur, 2020;Chowdhury et al, 2022;Rehwinkel and Gack, 2020;Seth et al, 2005). NF-κB is activated in several innate immune paradigms and is well known for its role in pathological conditions, where prolonged or profuse NF-κB activation in reactive immune or glial cells causes inflammation.…”

Bothrops lanceolatus snake venom impairs mitochondrial respiration and induces DNA release in human heart preparation

“…Amongst all the cytosolic DNA sensors, cyclic GMP-AMP synthase (cGAS), activating PLOS NEGLECTED TROPICAL DISEASES endoplasmic reticulum-resident Stimulator of interferon genes (STING) are probably the most explored pathway. This pathway is triggered during infection with cytosolic bacterial pathogens and some DNA viruses resulting into transcriptional induction of type I interferon and the nuclear factor-κB (dependent expression of proinflammatory cytokines [23].…”

HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System

“…Although it has been initially characterized in pathogen-infected cells, activation of IFN-I is now a well-established cellular response to damage-associated molecular patterns, which are abnormal molecules in the cytosolic compartment. These abnormal molecules include leaked fragments of nuclear DNA and mitochondrial DNA and dsRNA. , A recent report by Marzio et al (2022) provided strong evidence from experimental models and human clinical studies that INF-I response is regulated by KEAP1 as a separate function from its control of NRF2. Similar to its regulation of NRF2 in unstressed cells, KEAP1 was found to target a proto-oncogene EMSY for ubiquitin-mediated proteasomal degradation.…”

“…These abnormal molecules include leaked fragments of nuclear DNA and mitochondrial DNA and dsRNA. 100 , 101 A recent report by Marzio et al (2022) 33 provided strong evidence from experimental models and human clinical studies that INF-I response is regulated by KEAP1 as a separate function from its control of NRF2. Similar to its regulation of NRF2 in unstressed cells, KEAP1 was found to target a proto-oncogene EMSY for ubiquitin-mediated proteasomal degradation.…”