4/9/2023 0 Comments Protein scaffold in dna![]() Second, mitochondria have two membranes - the inner mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM) - which together offer a dual layer of control segregating mitochondrial DAMPs (mtDAMPs) from their cognate PRRs 18. For example, in contrast to nuclear DNA (but similarly to bacterial genomes), the mitochondrial genome is circular and not associated with histones 18. First, mitochondria are widely considered as the evolutionary remnants of ancestral Alphaproteobacteria (the ancestors of modern Gram-negative bacteria) 17, and some mitochondrial components have considerable similarity with bacterial molecules, suggesting that they might function as PRR ligands. On the basis of these considerations, it would seem likely that mitochondria have an important role in the control of inflammatory responses, for at least three reasons 16. For example, ATP functions as a DAMP only upon release into the extracellular environment when it can bind to cognate receptors expressed on myeloid cells, such as the purinergic receptors P2RY2 and P2RX7 (refs. However, cellular stress and death can be accompanied by considerable alterations in the permeability of various cellular compartments, which enables PRR activation by DAMPs and the consequent initiation of inflammatory responses 12. In physiological conditions, DAMPs - which include nucleic acids, small metabolites such as ATP and proteins such as calreticulin - are generally unable to drive PRR signalling because they cannot gain physical access to PRR-containing subcellular compartments 13. Importantly, PRRs can be activated not only by viral and bacterial molecules associated with infection - so-called microorganism-associated molecular patterns or pathogen-associated molecular patterns - but also by endogenous molecules that are commonly referred to as damage-associated molecular patterns (DAMPs) 12. Inflammation is generally initiated by the activation of pattern recognition receptors (PRRs) that are expressed by both immune and non-immune cells 12. These examples highlight the crucial requirement for regulated inflammatory responses in organismal development and homeostasis. Moreover, recent findings indicate that numerous components of the molecular cascades underlying inflammation are key for normal embryonic and postembryonic development, at least in specific settings such as neurodevelopment 11. For example, whereas indolent, chronic inflammation has been associated with oncogenesis and accelerated tumour progression in various settings 7, potent inflammatory responses culminating in the engagement of adaptive immunity underlie the beneficial effects of numerous cancer therapies, including conventional chemotherapeutics 8, targeted anticancer agents 9 and radiotherapy 10. Of note, inflammatory reactions may affect the course of specific diseases in opposing manners, largely depending on the intensity and duration of inflammation. Moreover, inefficient inflammatory reactions facilitate the persistence of infectious pathogens 5 and enable the emergence and progression of malignant lesions in the context of failing cancer immunosurveillance 6. On the other hand, uncontrolled inflammatory responses may aggravate the course of conditions that originate from non-inflammatory cues, such as myocardial infarction 3. On the one hand, disproportionate, unwarranted or unresolving inflammation can act as a bona fide disease driver, as in the case of chronic inflammatory bowel disease 1. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.ĭeregulated inflammatory responses are involved in numerous human disorders, encompassing not only infectious and autoimmune disorders but also neurological, cardiovascular, renal, hepatic and neoplastic conditions 1, 2, 3, 4. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu.
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