Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis

Ryu, Changwan; Sun, Huanxing; Gulati, Mridu; Herazo-Maya, José D.; Chen, Yonglin; Osafo-Addo, Awo; Brandsdorfer, Caitlin; Winkler, Julia; Blaul, Christina; Faunce, Jaden; Pan, Heng; Woolard, Tony; Tzouvelekis, Argyrios; Antin‐Ozerkis, Danielle; Puchalski, Jonathan; Slade, Martin D.; Gonzalez, Anjelica L.; Bogenhagen, Daniel F.; Kirillov, Varvara; Feghali‐Bostwick, Carol; Gibson, Kevin F.; Lindell, Kathleen O.; Herzog, Raimund I.; Cruz, Charles S. Dela; Mehal, Wajahat Z.; Kaminski, Naftali; Herzog, Erica L.; Trujillo, Glenda

doi:10.1164/rccm.201612-2480oc

Cited by 142 publications

(150 citation statements)

References 51 publications

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“…Another important pathological feature of mitochondrial dysfunction is the cellular release of fragmented, oxidised mtDNA, which acts as danger associated molecular pattern (DAMP) . IPF‐LFs in culture, when compared to Ctrl‐LF, release increased amounts of mtDNA . Furthermore, BALF and serum levels of mtDNA are higher in patients with IPF, as compared to control donors, with serum levels being predictive of all‐cause mortality …”

Section: Discussionmentioning

confidence: 99%

“…IPF‐LFs in culture, when compared to Ctrl‐LF, release increased amounts of mtDNA . Furthermore, BALF and serum levels of mtDNA are higher in patients with IPF, as compared to control donors, with serum levels being predictive of all‐cause mortality …”

Section: Discussionmentioning

confidence: 99%

“…33 IPF-LFs in culture, when compared to Ctrl-LF, release increased amounts of mtDNA. 34 Furthermore, BALF and serum levels of mtDNA are higher in patients with IPF, as compared to control donors, with serum levels being predictive of all-cause mortality. 34 In addition to respiratory decoupling, elevated levels of mitochondrial superoxide in IPF-LFs could also be a consequence of increases in mitochondrial mass.…”

Section: Discussionmentioning

confidence: 99%

“…34 Furthermore, BALF and serum levels of mtDNA are higher in patients with IPF, as compared to control donors, with serum levels being predictive of all-cause mortality. 34 In addition to respiratory decoupling, elevated levels of mitochondrial superoxide in IPF-LFs could also be a consequence of increases in mitochondrial mass. The dysregulation of mitochondrial biogenesis, fusion, fission and mitophagy all contribute to changes in the mitochondrial pool in ageing and disease.…”

Section: Discussionmentioning

confidence: 99%

“…The dysregulation of mitochondrial biogenesis, fusion, fission and mitophagy all contribute to changes in the mitochondrial pool in ageing and disease. 19,23,34,35 Increased mitochondrial mass is reported in AECII and lung fibroblasts in IPF and airway smooth muscle (ASM) cells in severe asthma. 23,36,37 In this study, increased levels of mtDNA and MitoTracker Green staining suggest IPF-LFs also exhibit a net increase in mitochondrial mass as compared to Ctrl-LFs, possibly a consequence of increased biogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

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et al. 2018

J Cellular Molecular Medi

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Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF‐LFs). Primary cultures of IPF‐LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐LFs). Furthermore, IPF‐LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF‐LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐LFs, but not IPF‐LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF‐LF senescence and/or attenuated pharmacologically induced Ctrl‐LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto‐amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

Read

et al. 2018

J Cellular Molecular Medi

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DNA‐Based Biomaterials for Immunoengineering

Maeda

Kojima

Song

et al. 2018

Adv Healthcare Materials

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of extracellular DNA in tissues and in circulation. [5] Extracellular DNA is capable of engaging with the immune system as depicted in Figure 1; therefore, as synthetic DNA-based biomaterials emerge, their potential immune responses must be considered. DNA sensors are mediators of extracellular DNA immune responses observed in vivo, including cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and toll-like receptors (TLRs). Defining novel DNA sensors and their mechanisms is an active area of investigation. [6] Likewise, the structural and chemical properties of DNA that triggers DNA sensors continue to be uncovered. [6] This review summarizes known DNA interaction modalities with the immune system, the sources of extracellular DNA, and, finally, the relevant and emerging biotechnologies that incorporate DNA molecules. A focus is geared toward innate immune responses and doublestranded DNA (dsDNA). Leveraging the immunomodulatory capacity of DNA enables tailoring materials to initiate specific immune outcomes depending on the application, for instance, priming aggressive immune responses for localized tumor-interfacing biomaterials or immunosuppressive functions to prevent chronic inflammation on implant surfaces. Achieving this requires an improved understanding of the DNA properties, such as backbone chemistry, base pair sequence, charge, and length, that can function as design levers for the immune response. The Role of Extracellular DNA in the Immune ResponseThe immune system is designed to protect the host against infections by distinguishing between self-and non-self motifs, and by identifying pathogen and damage signals. Upon recognition of a "non-self" or foreign molecule, an array of effector functions are triggered and orchestrated by immune cells to achieve pathogen clearance and restore homeostasis. [7] These immunoactivating defense mechanisms include the release of proinflammatory cytokines, immune cell recruitment, programmed cell death, and phagocytosis. Ideally, immunoactivating responses are supplanted by immunosuppressive functions once the pathogen or agonist is resolved. This immune resolution is necessary to coordinate healing and anti-inflammatory functions such as diminished chemokine and cytokine secretion, replacement Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNAbased biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage-associated molecular patterns (DAMPs), or pathogen-associated mole...

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Self‐Propelled Proteomotors with Active Cell‐Free mtDNA Clearance for Enhanced Therapy of Sepsis‐Associated Acute Lung Injury

et al. 2023

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Acute lung injury (ALI) is a frequent and serious complication of sepsis with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis‐associated ALI can help develop new therapeutic strategies. Herein, the crucial role of cell‐free mitochondrial DNA (cf‐mtDNA) in the regulation of alveolar macrophage activation during sepsis‐associated ALI is identified. Most importantly, a biocompatible hybrid protein nanomotor (NM) composed of recombinant deoxyribonuclease I (DNase‐I) and human serum albumin (HSA) via glutaraldehyde‐mediated crosslinking is prepared to obtain an inhalable nanotherapeutic platform targeting pulmonary cf‐mtDNA clearance. The synthesized DNase‐I/HSA NMs are endowed with self‐propulsive capability and demonstrate superior performances in stability, DNA hydrolysis, and biosafety. Pulmonary delivery of DNase‐I/HSA NMs effectively eliminates cf‐mtDNAs in the lungs, and also improves sepsis survival by attenuating pulmonary inflammation and lung injury. Therefore, pulmonary cf‐mtDNA clearance strategy using DNase‐I/HSA NMs is considered to be an attractive approach for sepsis‐associated ALI.

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Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis

Abstract: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

Cited by 142 publications

References 51 publications

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

DNA‐Based Biomaterials for Immunoengineering

Self‐Propelled Proteomotors with Active Cell‐Free mtDNA Clearance for Enhanced Therapy of Sepsis‐Associated Acute Lung Injury

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