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.

Keywords: disease; innate immunity; mitochondrial—nuclear exchange; mitochondrion; signaling.

FIGURE 1

Pathways of nucleo-mitochondrial communication. Nucleus-to-mitochondrion signals make up anterograde signaling. Signals from the mitochondria constitute the retrograde signaling. The integrated stress response is a general cellular stress pathway which can be triggered in ER, mitochondria or cytosol. Lastly, mito-nuclear crosstalk is the ability to orchestrate bidirectional feedback responses, they usually originate in mitochondria and result in nuclear responses.

FIGURE 2

Mitochondrial DAMPs can trigger the innate immunity through various pathways. Intra-cellular signals include the sensing of the mitochondrial nucleic acids, mtRNA or mtDNA, resulting into IRF3 or NFKB mediated T1-IFN response. Alternatively, TLR receptors on the autophagosome can sense mitochondrial nucleic acids and through TRIF/MyD88 stimulate the T1-IFN signaling. Free mtDNA can also stimulate the inflammasome for IL-1B production. DAMPs can also stimulate their respective receptors on other cells through extra-cellular signaling.

FIGURE 3

Models of mitochondrial nucleic acids release and respective intracellular sensors and effectors. Domain abbreviations: Caspase activation and recruitment domains (CARD), C-terminal regulatory domain (CTD), Transmembrane (TM), Nucleotidyltransferase (NTase), Zinc ribbon insertion (Zn), Receptor-interacting protein (RIP) Homotypic interaction motifs (RHIM), Pyrin domain (PYD), Hematopoietic interferon-inducible nuclear protein with 200-amino-acid repeats (HIN200), Dimerization domain (DD), Cyclic dinucleotide (CDN) binding domain (CBD), C-terminal Tail (CTT).

FIGURE 4

Comparison of anti-viral and mitochondrial nucleic acid responses. Both lead to a prolonged T1-IFN inflammatory response. However, in case of mitochondrial nucleic acid sensing pathways, the overactivation of inflammation leads to systemic/organ-specific auto-immune diseases or even fibrosis in various organs.