Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Lei, Yuanjiu; Martinez, Camila Guerra; Torres-Odio, Sylvia; Bell, Samantha L.; Birdwell, Christine; Bryant, Joshua D.; Tong, Carl W.; Watson, Robert O.; West, Laura Ciaccia; West, A. Phillip

doi:10.1101/2020.09.22.308171

Cited by 3 publications

(2 citation statements)

References 88 publications

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“…Various stresses such as mtDNA damage, defects in mtDNA maintenance factors ( 80 ), ROS, or microbial invasions ( 185 ) can result in the release of mtDNA into the cytosol, where it can come in contact with and trigger PRRs. The main route involved in the recognition of mtDNA in the cytosol is the cGAS-STING (stimulator of interferon genes) pathway, responsible for detecting the presence of invading DNA.…”

Section: Mtdna Release and Inflammationmentioning

confidence: 99%

Mitochondrial DNA Instability in Mammalian Cells

Carvalho

Repolês

Mendes

et al. 2022

Antioxidants & Redox Signaling

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Significance: The small, multicopy mitochondrial genome (mtDNA) is essential for efficient energy production, as alterations in its coding information or a decrease in its copy number disrupt mitochondrial ATP synthesis. However, the mitochondrial replication machinery encounters numerous challenges that may limit its ability to duplicate this important genome and that jeopardize mtDNA stability, including various lesions in the DNA template, topological stress and an insufficient nucleotide supply.Recent Advances: An ever-growing array of DNA repair or maintenance factors are being reported to localize to the mitochondria. We review current knowledge regarding the mitochondrial factors that may contribute to the tolerance or repair of various types of changes in the mitochondrial genome, such as base damage, incorporated ribonucleotides and strand breaks. We also discuss the newly-discovered link between mtDNA instability and activation of the innate immune response. Critical Issues: By which mechanisms do mitochondria respond to challenges that threaten mtDNA maintenance? What types of mtDNA damage are repaired, and when are the affected molecules degraded instead? And, finally, which forms of mtDNA instability trigger an immune response, and how? Future Directions: Further work is required to understand the contribution of the DNA repair and damage-tolerance factors present in the mitochondrial compartment, as well as the balance between mtDNA repair and degradation. Finally, efforts to understand the events underlying mtDNA release into the cytosol are warranted. Pursuing these and many related avenues can improve our understanding of what goes wrong in mitochondrial disease.

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Section: Mtdna Release and Inflammationmentioning

confidence: 99%

Mitochondrial DNA Instability in Mammalian Cells

Carvalho

Repolês

Mendes

et al. 2022

Antioxidants & Redox Signaling

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“…upon loss of the mitochondrial proteases CLPP and YMEL1 ( 56 , 111 ). Similarly, multisystemic dysfunction caused by mtDNA mutation accumulation in the proofreading-deficient POLG mutator mouse can be rescued by ablation of cGAS-STING activity or IFN signaling ( 112 ). Whether maladaptive inflammation is observed in the corresponding human mitochondrial diseases has not been explored.…”

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

2021

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The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.

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Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance

Yabaji,

Zhernovkov,

Araveti

et al. 2024

Preprint

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A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop clinical, mostly pulmonary, TB. To dissect mechanisms of susceptibility in immunocompetent individuals, we developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: development of necrotic lung lesions after infection with virulent Mtb. In this study, we explored the connectivity of the sst1-regulated pathways during prolonged macrophage activation with TNF. We determined that the aberrant response of the sst1-susceptible macrophages to TNF was primarily driven by conflicting Myc and antioxidant response pathways that resulted in a coordinated failure to properly sequester intracellular iron and activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled IFN[beta] superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. Our findings suggest a novel link between metabolic dysregulation in macrophages and susceptibility to TB, offering insights into potential therapeutic targets aimed at modulating macrophage function and improving TB control.

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Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Cited by 3 publications

References 88 publications

Mitochondrial DNA Instability in Mammalian Cells

Mitochondrial DNA Instability in Mammalian Cells

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance

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