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.
Highlights
Mitochondria play an essential role in generating cellular energy and contain the oxidative phosphorylation (OXPHOS) system
Shorter DNA of approx. 20 bp can bind to cGAS, but longer double-stranded DNA (dsDNA) of more than 45 bp can form more stable ladder-like networks of cGAS dimers, which leads to stronger enzymatic activity (Li et al, 2013) (Zhang J.-Z et al, 2014) After the DNA binding, the catalytic pocket of cGAS is accessible for synthesis of cyclic GMP–AMP (cGAMP) by converting GTP and Adenosine triphosphate (ATP) into cGAMP
In pathophysiology of non-alcoholic fatty liver disease (NAFLD), the potential induction of TLR9 signaling by mtDNA seems to play a role, since Garcia-Martinez et al were the first to show a direct link between the release of oxidized mitochondrial DNA from hepatocytes and its recognition by TLR9 in humans and in mouse model (Garcia-Martinez et al, 2016)
Summary
Mitochondria play an essential role in generating cellular energy and contain the oxidative phosphorylation (OXPHOS) system. Primary mitochondrial disorders are a complex group of metabolic impairments caused by flaws or deficiencies in one or more components of the OXPHOS. All these defects manifest in mitochondrial dysfunction which is sensed and communicated through. Defects in OXPHOS metabolism result in the trigger of mitochondrial nucleic acid sensing pathways (Lei et al, 2021; Sprenger et al, 2021). To unravel this complex interaction, it is necessary to decipher how mitochondria communicate with the immune system
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