scholarly journals Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response

2015 ◽  
Vol 108 (2) ◽  
pp. 3a
Author(s):  
Phillip West
2021 ◽  
Author(s):  
Xiucui Ma ◽  
David R Rawnsley ◽  
Attila Kovacs ◽  
Moydul Islam ◽  
John T Murphy ◽  
...  

Mitochondrial damage triggers cell death signaling with catastrophic consequences in long-lived and irreplaceable cells, such as cardiac myocytes. Sensing of leaked mitochondrial DNA upon mitochondrial damage is also a potent trigger of inflammation. Whether the innate immune response pathways monitor mitochondrial damage in mitochondria-rich cardiac myocytes to prevent inflammation and cell death, remains unknown. TRAF2, an adaptor protein downstream of innate immune receptors, localizes to the mitochondria in the unstressed heart, with increased mitochondrial targeting in cardiomyopathic human hearts and after cardiac ischemia-reperfusion injury in mice. Inducible cardiomyocyte-specific deletion of TRAF2 in young adult mice impairs mitophagy with rapid decline in mitochondrial quality, upregulates TLR9 expression in cardiac myocytes, and results in inflammation and cell death manifesting as a fulminant cardiomyopathy. Preventing TLR9-mediated mitochondrial DNA sensing and resultant inflammation provides a short-term reprieve from cardiomyopathy, but persistence of damaged mitochondria results in long-term recrudescence. Restoration of TRAF2, but not the E3 ubiquitin ligase deficient mutant improves mitochondrial quality and rescues cardiomyopathy to restore homeostasis. Thus, the innate immune response acts via TRAF2 as the first line of defense against mitochondrial damage by orchestrating homeostatic mitophagy to dampen myocardial inflammation and prevent cell death.


2020 ◽  
Vol 48 (6) ◽  
pp. 2823-2838
Author(s):  
Palamou Das ◽  
Oishee Chakrabarti

Mitochondrial DNA (mtDNA) can initiate an innate immune response when mislocalized in a compartment other than the mitochondrial matrix. mtDNA plays significant roles in regulating mitochondrial dynamics as well as mitochondrial unfolded protein response (UPR). The mislocalized extra-mtDNA can elicit innate immune response via cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) pathway, inducing the expression of the interferon-stimulated genes (ISGs). Also, cytosolic damaged mtDNA is cleared up by various pathways which are responsible for participating in the activation of inflammatory responses. Four pathways of extra-mitochondrial mtDNA clearance are highlighted in this review — the inflammasome activation mechanism, neutrophil extracellular traps formation, recognition by Toll-like receptor 9 and transfer of mtDNA between cells packaged into extracellular vesicles. Anomalies in these pathways are associated with various diseases. We posit our review in the present pandemic situation and discuss how mtDNA elicits innate immune responses against different viruses and bacteria. This review gives a comprehensive picture of the role of extra-mitochondrial mtDNA in infectious diseases and speculates that research towards its understanding would help establish its therapeutic potential.


Nature ◽  
2015 ◽  
Vol 520 (7548) ◽  
pp. 553-557 ◽  
Author(s):  
A. Phillip West ◽  
William Khoury-Hanold ◽  
Matthew Staron ◽  
Michal C. Tal ◽  
Cristiana M. Pineda ◽  
...  

2015 ◽  
Vol 29 (3) ◽  
pp. 119-129 ◽  
Author(s):  
Richard J. Stevenson ◽  
Deborah Hodgson ◽  
Megan J. Oaten ◽  
Luba Sominsky ◽  
Mehmet Mahmut ◽  
...  

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.


Sign in / Sign up

Export Citation Format

Share Document