Mitochondria and pathogen immunity: from killer to firestarter

Riley, Joel S.; Tait, Stephen W.G.

doi:10.15252/embj.2019102325

Cited by 12 publications

(8 citation statements)

References 12 publications

(14 reference statements)

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“…Indeed, we have recently found in vitro that infection of epithelial cell lines and fibroblasts with not only any of the three viruses tested but also the two bacterial species, as well as one protozoan parasite, triggered sub-lethal signals at the mitochondria [ 19 ]. We believe that this is relevant, because the signals generated in the apoptotic pathway contributed to the secretion of soluble pro-inflammatory products [ 19 , 56 ]. As we will discuss further below, such signals may be a convenient way for the organism to initiate an inflammatory and immune response.…”

Section: A Possible Function Of Mitochondrial Sub-lethal Signals In I...mentioning

confidence: 99%

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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One of the tasks of mitochondria is the rule over life and death: when the outer membrane is permeabilized, the release of intermembrane space proteins causes cell death by apoptosis. For a long time, this mitochondrial outer membrane permeabilization (MOMP) has been accepted as the famous step from which no cell returns. Recent results have however shown that this quite plainly does not have to be the case. A cell can also undergo only a little MOMP, and it can efficiently repair damage it has incurred in the process. There is no doubt now that such low-scale permeabilization occurs. A major unclarified issue is the biological relevance. Is small-scale mitochondrial permeabilization an accident, a leakiness of the apoptosis apparatus, perhaps during restructuring of the mitochondrial network? Is it attempted suicide, where cell death by apoptosis is the real goal but the stimulus failed to reach the threshold? Or, more boldly, is there a true biological meaning behind the event of the release of low amounts of mitochondrial components? We will here explore this last possibility, which we believe is on one hand appealing, on the other hand plausible and supported by some evidence. Recent data are consistent with the view that sub-lethal signals in the mitochondrial apoptosis pathway can drive inflammation, the first step of an immune reaction. The apoptosis apparatus is almost notoriously easy to trigger. Sub-lethal signals may be even easier to set off. We suggest that the apoptosis apparatus is used in this way to sound the call when the first human cell is infected by a pathogen.

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Section: A Possible Function Of Mitochondrial Sub-lethal Signals In I...mentioning

confidence: 99%

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Häcker

Haimovici

2022

Cell Death Differ

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“…To date, most of what we know about mitochondrion-driven innate immunity relates to the ability of mito-DAMPs (e.g., mtDNA, cardiolipin, formyl-methionine-labeled peptides, and cytochrome c) to engage pattern recognition receptors and trigger cytokine/chemokine production and/or cell death. Because the role of mito-DAMPs in eliciting immune responses has been reviewed extensively elsewhere (9,(36)(37)(38), we will focus here on mtDNA, the mito-DAMP that we currently know the most about during Mtb infection.…”

Section: Mitochondrial Damps and Mtb Trigger Many Of The Same Innate Immune Responsesmentioning

confidence: 99%

Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection

Patrick

Watson

2021

Infect Immun

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Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for crosstalk or synergy between bacteria- and mitochondria-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking—and intriguing—in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages leading to metabolic changes and triggering potent innate immune responses. Research from our labs and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyper-activating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrial-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

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“…34 STING is particularly prone to activation in the context of viral or bacterial infection, at least in part reflecting (1) the elevated sensitivity of CGAS for histone-free DNA, 35,36 and (2) the direct contribution of bacterial CDNs to STING. 25,26 However, STING can also be triggered by the cytosolic accumulation of endogenous DNA of both nuclear [37][38][39] and more so mitochondrial [40][41][42][43][44] origin. Thus, cancer cells undergoing DNA damage and mitochondrial outer membrane permeabilization (MOMP) 45 in response to chemotherapy or radiation therapy are likely to secrete type I interferon (IFN) and other STING-dependent cytokines, [46][47][48] although the MOMP-driven activation of apoptotic caspases considerably inhibits the process.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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Mitochondria and pathogen immunity: from killer to firestarter

Cited by 12 publications

References 12 publications

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Sub-lethal signals in the mitochondrial apoptosis apparatus: pernicious by-product or physiological event?

Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection

Trial watch: STING agonists in cancer therapy

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