Mitochondrial control of inflammation

REVIEWS Mitochondrial control of inflammation Saverio Marchi 1,7, Emma Guilbaud and Lorenzo Galluzzi 2,5,6 ✉ , Stephen W. G. Tait 2,7 , Takahiro Yamazaki2 ✉ 3,4 Abstract | Numerous mitochondrial constituents and metabolic products can function as damageassociated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. 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. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. 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. Cancer immunosurveillance A process through which the immune system recognizes and eliminates the majority of newly formed cancer cell precursors, hence suppressing oncogenesis. 1 Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy. 2 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. 3 Cancer Research UK Beatson Institute, Glasgow, UK. 4 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 5 Sandra and Edward Meyer Cancer Center, New York, NY, USA. 6 Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. 7 These authors contributed equally: Saverio Marchi, Emma Guilbaud. ✉e-mail: ; https://doi.org/10.1038/ s41577-022-00760-x Deregulated inflammatory responses are involved in numerous human disorders, encompassing not only infectious and autoimmune disorders but also neuro logical, cardiovascular, renal, hepatic and neoplas tic conditions1–4. On the one hand, disproportionate, unwarranted or unresolving inflammation can act as a bona fide disease driver, as in the case of chronic inflam matory bowel disease1. On the other hand, uncontrolled inflammatory responses may aggravate the course of conditions that originate from non-inflammatory cues, such as myocardial infarction3. Moreover, inefficient inflammatory reactions facilitate the persistence of infectious pathogens5 and enable the emergence and progression of malignant lesions in the context of fail ing cancer immunosurveillance6. Of note, inflammatory reactions may affect the course of specific diseases in opposing manners, largely depending on the intensity and duration of inflammation. For example, whereas indolent, chronic inflammation has been associated with oncogenesis and accelerated tumour progression in various settings7, potent inflammatory responses culmi nating in the engagement of adaptive immunity under lie the beneficial effects of numerous cancer therapies, including conventional chemotherapeutics8, targeted anticancer agents9 and radiotherapy10. 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 neurodevelopment11. These examples highlight the crucial requirement for regulated inflammatory responses in organismal development and homeostasis. Nature Reviews | Immunology 0123456789();: Inflammation is generally initiated by the activa tion of pattern recognition receptors (PRRs) that are expressed by both immune and non-immune cells12. 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. In physiological conditions, DAMPs — which include nucleic acids, small metabolites such as ATP and pro teins such as calreticulin — are generally unable to drive PRR signalling because they cannot gain physical access to PRR-containing subcellular compartments13. 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 responses12. 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.14,15). 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 reasons16. First, mitochondria are widely considered as the evolutionary remnants of ances tral Alphaproteobacteria (the ancestors of modern Gram-negative bacteria)17, and some mitochondrial components have considerable similarity with bacte rial molecules, suggesting that they might function as Reviews Box 1 | Regulation of cell death by mitochondria Mitochondrial outer membrane permeabilization (MOMP), as initiated by the proapoptotic pore-forming proteins BCL-2-associated X, apoptosis regulator (BaX) and BCL-2 antagonist/killer 1 (BaK1), is a key step in at least two types of caspase-dependent regulated cell death: intrinsic apoptosis, and extrinsic apoptosis in type II cells (such as hepatocytes)19. irrespective of whether the lethal stimulus originates from the intracellular microenvironment or the extracellular microenvironment, MOMP enables the trans location of cytochrome c from the mitochondrial intermembrane space to the cytosol. this results in the assembly of an apoptotic peptidase-activating factor 1 (aPaF1)- and caspase 9 (CasP9)-containing supramolecular complex that is commonly known as the apoptosome and elicits activation of the ‘executioner’ caspase CasP3 as one of the final steps in the apoptotic cascade45. in physiological conditions, MOMP is actively prevented by anti-apoptotic members of the BCL-2 protein family, including BCL-2 itself as well as BCL-2-like protein 1 (BCL-2L1; best known as BCL-XL) and MCL1. However, in the presence of an apoptotic stimulus, the transcriptional or post-translational activation of BH3-only proteins, such as BH3-interacting domain death agonist (BiD) or BCL-2-binding component 3 (BBC3; best known as PuMa), culminates in the activation of proapoptotic members of the BCL-2 family, such as BaX and BaK1, which oligomerize into the outer mitochondrial membrane to precipitate MOMP. Of note, BaX and BaK1 activation by BH (...truncated)