scholarly journals SIRT3 Overexpression Ameliorates Asbestos-Induced Pulmonary Fibrosis, mt-DNA Damage and Lung Fibrogenic Monocyte Recruitment

2021 ◽  
Vol 22 (13) ◽  
pp. 6856
Author(s):  
Paul Cheresh ◽  
Seok-Jo Kim ◽  
Renea Jablonski ◽  
Satoshi Watanabe ◽  
Ziyan Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pulmonary Fibrosis ◽  
Cell Fate ◽  
Lung Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Mitochondrial Protein ◽  
Whole Body ◽  
Dependent Manner ◽  
Mt Dna ◽  
Mtdna Damage

Alveolar epithelial cell (AEC) mitochondrial (mt) DNA damage and fibrotic monocyte-derived alveolar macrophages (Mo-AMs) are implicated in the pathobiology of pulmonary fibrosis. We showed that sirtuin 3 (SIRT3), a mitochondrial protein regulating cell fate and aging, is deficient in the AECs of idiopathic pulmonary fibrosis (IPF) patients and that asbestos- and bleomycin-induced lung fibrosis is augmented in Sirt3 knockout (Sirt3−/−) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (Sirt3Tg) protects mice from asbestos-induced pulmonary fibrosis by mitigating lung mtDNA damage and Mo-AM recruitment. Crocidolite asbestos (100 µg/50 µL) or control was instilled intratracheally in C57Bl6 (Wild-Type) mice or Sirt3Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3Tg mice were protected from asbestos-induced pulmonary fibrosis and had diminished lung mtDNA damage and Mo-AM recruitment. Further, pharmacologic SIRT3 inducers (i.e., resveratrol, viniferin, and honokiol) each diminish oxidant-induced AEC mtDNA damage in vitro and, in the case of honokiol, protection occurs in a SIRT3-dependent manner. We reason that SIRT3 preservation of AEC mtDNA is a novel therapeutic focus for managing patients with IPF and other types of pulmonary fibrosis.

scholarly journals Mitochondrial 8-oxoguanine DNA glycosylase mitigates alveolar epithelial cell PINK1 deficiency, mitochondrial DNA damage, apoptosis, and lung fibrosis

2020 ◽  
Vol 318 (5) ◽  
pp. L1084-L1096 ◽  
Author(s):  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Renea P. Jablonski ◽  
Lyudmila Rachek ◽  
Anjana Yeldandi ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Excision Repair ◽  
Alveolar Epithelial Cell ◽  
Mitochondrial Protein ◽  
Dna Glycosylase ◽  
Alveolar Type ◽  
Mtdna Damage ◽  
Alveolar Epithelial

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene ( mtOgg1tg) are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout ( Pink1-KO) mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.

ID: 140: KLOTHO, AN ANTI-AGING MOLECULE, REGULATES ALVEOLAR EPITHELIAL CELL MTDNA DAMAGE AND APOPTOSIS

2016 ◽  
Vol 64 (4) ◽  
pp. 961.1-961
Author(s):  
S Kim ◽  
P Cheresh ◽  
RP Jablonski ◽  
DW Kamp ◽  
M Eren ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Oxidative Dna Damage ◽  
Alveolar Epithelial Cell ◽  
Premature Aging ◽  
Protective Effects ◽  
Mtdna Damage ◽  
Alveolar Epithelial

RationaleConvincing evidence has emerged that impaired alveolar epithelial cell (AEC) injury and repair resulting from ‘exaggerated’ lung aging and mitochondrial dysfunction are critical determinants of the lung fibrogenic potential of toxic agents, including asbestos fibers, but the mechanisms underlying these findings is unknown. We showed that the extent of AEC mitochondrial DNA (mtDNA) damage and apoptosis are critical determinants of asbestos-induced pulmonary fibrosis (Cheresh et al AJRCMB 2014, Kim et al JBC 2014). Klotho is an age-inhibiting gene and Klotho-deficient mice demonstrate a premature aging phenotype that includes a reduced lifespan, arteriosclerosis, and lung oxidative DNA damage, and that Klotho attenuates hyperoxic-induced AEC DNA damage and apoptosis (Ravikumar et al AJP-Lung 2014). We reason that Klotho has an important role in limiting pulmonary fibrosis by protecting the AECs from oxidative stress.MethodsQuantitative PCR-based measurement of mtDNA damage was assessed following transient transfection with wild-type Klotho, Klotho siRNA or AKT siRNA in A549 and/or MLE-12 cells for 48 hrs followed by exposure to either amosite asbestos (25 µg/cm2) or H2O2 (200 µM) for 24 hrs. Apoptosis was assessed by cleaved caspase-9/3 levels and DNA fragmentation assay. Murine pulmonary fibrosis was analyzed in male 8–10 week old WT (C3H/C57B6J) mice or Klotho heterozygous knockout (Kl+/−) mice following intratracheal instillation of a single dose of 100 µg crocidolite asbestos or titanium dioxide (negative control) using histology (fibrosis score by Masson's trichrome staining) and lung collagen (Sircoll assay).ResultsCompared to control, amosite asbestos or H2O2 reduces Klotho mRNA/protein expression. Notably, silencing of Klotho promotes oxidative stress-induced AEC mtDNA damage and apoptosis whereas Klotho-enforced expression (EE) and Euk-134, a mitochondrial ROS scavenger, are protective. Interestingly, Kl+/− mice have increased asbestos-induced lung fibrosis. Also, we find that inhibition or silencing of AKT augments oxidant-induced AEC mtDNA damage and apoptosis.ConclusionsOur data demonstrate a crucial role for AEC AKT signaling in mediating the mtDNA damage protective effects of Klotho. Given the importance of AEC aging and apoptosis in pulmonary fibrosis, we reason that Klotho/AKT axis is an innovative therapeutic target for preventing common lung diseases of aging (i.e. IPF, COPD, lung cancer, etc.) for which more effective management regimens are clearly needed.FundingNIH-RO1 ES020357-01A1 (DK) and VA Merit (DK).

scholarly journals SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage

2017 ◽  
Vol 312 (1) ◽  
pp. L68-L78 ◽  
Author(s):  
Samik Bindu ◽  
Vinodkumar B. Pillai ◽  
Abhinav Kanwal ◽  
Sadhana Samant ◽  
Gökhan M. Mutlu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Lung Fibroblasts ◽  
Whole Body ◽  
Myofibroblast Differentiation ◽  
Mitochondrial Dna Damage

Myofibroblast differentiation is a key process in the pathogenesis of fibrotic diseases. Transforming growth factor-β1 (TGF-β1) is a powerful inducer of myofibroblast differentiation and is implicated in pathogenesis of tissue fibrosis. This study was undertaken to determine the role of mitochondrial deacetylase SIRT3 in TGF-β1-induced myofibroblast differentiation in vitro and lung fibrosis in vivo. Treatment of human lung fibroblasts with TGF-β1 resulted in increased expression of fibrosis markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. TGF-β1 treatment also caused depletion of endogenous SIRT3, which paralleled with increased production of reactive oxygen species (ROS), DNA damage, and subsequent reduction in levels of 8-oxoguanine DNA glycosylase (OGG1), an enzyme that hydrolyzes oxidized guanine (8-oxo-dG) and thus protects DNA from oxidative damage. Overexpression of SIRT3 by adenovirus-mediated transduction reversed the effects of TGF-β1 on ROS production and mitochondrial DNA damage and inhibited TGF-β1-induced myofibroblast differentiation. To determine the antifibrotic role of SIRT3 in vivo, we used the bleomycin-induced mouse model of pulmonary fibrosis. Compared with wild-type controls, Sirt3-knockout mice showed exacerbated fibrosis after intratracheal instillation of bleomycin. Increased lung fibrosis was associated with decreased levels of OGG1 and concomitant accumulation of 8-oxo-dG and increased mitochondrial DNA damage. In contrast, the transgenic mice with whole body Sirt3 overexpression were protected from bleomycin-induced mtDNA damage and development of lung fibrosis. These data demonstrate a critical role of SIRT3 in the control of myofibroblast differentiation and lung fibrosis.

ID: 117: SIRT3, THE MAJOR ANTI-AGING MITOCHONDRIAL DEACETYLASE, IS IMPORTANT FOR PREVENTING PULMONARY FIBROSIS

2016 ◽  
Vol 64 (4) ◽  
pp. 967.1-967
Author(s):  
RP Jablonski ◽  
S Kim ◽  
P Cheresh ◽  
DB Williams ◽  
DW Kamp
Keyword(s):  
Pulmonary Fibrosis ◽  
Mitochondrial Function ◽  
Lung Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Asbestos Exposure ◽  
Parenchymal Cell ◽  
Lung Compliance ◽  
Negative Control ◽  
Pilot Studies ◽  
Mtdna Damage

ObjectivesAlveolar epithelial cell (AEC) injury from ‘exaggerated’ lung aging and mitochondrial dysfunction play vital roles in the development of lung fibrosis. Our group, using the asbestos lung fibrosis paradigm, has shown that AEC mitochondrial reactive oxygen species (ROS) mediate asbestos-induced AEC mitochondrial DNA (mtDNA) damage and apoptosis by a mitochondria-regulated (intrinsic) death pathway. Sirtuin 3 (SIRT3), the anti-aging major mitochondrial deacetylase governing mitochondrial function, mitigates oxidative stress and fibrosis in non-lung models though deacetylation of diverse substrates including MnSOD (Chen et al EMBO Rep 2011) and OGG1 (Cheng et al Cell Death Dis 2013). We previously reported that SIRT3 deficient (Sirt3−/−) mice have increased lung fibrosis following asbestos exposure associated with exaggerated AEC mtDNA damage and apoptosis. Herein, we determined whether SIRT3 deficiency augments bleomycin-induced lung fibrosis and whether AEC acetylation is increased in lung biopsy samples from patients with idiopathic pulmonary fibrosis (IPF).MethodsMale 8- to 10- week-old 129SJ (Sirt3+/+) and Sirt3−/− mice were treated with a single intratracheal instillation of saline or bleomycin (0.01U). At 3 weeks, the lungs were harvested for various endpoints including Sircol collagen assay, fibrosis scoring and measurement of lung compliance. Specimens from explanted lungs of patients with IPF were subject to immunohistochemistry with antibodies to MnSODK68, Ac-OGG1 and IgG (negative control) to assess acetylation.ResultsCompared to wild type, Sirt3−/− mice developed increased pulmonary fibrosis following bleomycin exposure as measured by fibrosis score (7.8 vs. 11.25, p<0.05), Sircol assay (0.90 vs. 1.35, p<0.05) and lung compliance (0.0688 mL/cmH2O vs. 0.0449 mL/cm H2O, p<0.05). Notably, increased expression of MnSODK68 and Ac-OGG1 was evident in the lungs of patients with IPF. Co-localization studies evaluating MnSODK68 and SFPTC are ongoing.ConclusionsSIRT3 deficiency enhances bleomycin-induced pulmonary fibrosis in a manner similar to asbestos fibers. An important role for augmented human IPF lung parenchymal cell mitochondrial acetylation is suggested by our pilot studies. Taken together, this suggests that SIRT3 plays a key role in the pathogenesis of IPF in part by preserving AEC mitochondrial function and mtDNA through modulation of the SIRT3/ACO-2/OGG1/apoptosis axis. Given the crucial role for aging in IPF as well as changes in SIRT3 expression with aging, our findings suggest a novel therapeutic target for modulating lung fibrosis.FundingVA Merit and NIH R01 ES02037-01A1 (DK), NIH/NHLBI T32 HL076139-11A1 (RJ).

scholarly journals The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes

2020 ◽  
Vol 21 (16) ◽  
pp. 5595
Author(s):  
Paul Cheresh ◽  
Seok-Jo Kim ◽  
Long Shuang Huang ◽  
Satoshi Watanabe ◽  
Nikita Joshi ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Sphingosine Kinase ◽  
Lung Epithelial Cell ◽  
Lung Fibroblasts ◽  
Sphingosine Kinase 1 ◽  
Mtdna Damage ◽  
Lung Epithelial ◽  
Monocyte Recruitment

Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7−21 following bleomycin and day 14−21 or day 30−60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.

scholarly journals SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis

2017 ◽  
Vol 31 (6) ◽  
pp. 2520-2532 ◽  
Author(s):  
Renea P. Jablonski ◽  
Seok‐Jo Kim ◽  
Paul Cheresh ◽  
David B. Williams ◽  
Luisa Morales‐Nebreda ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Epithelial Cell ◽  
Lung Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Mitochondrial Dna Damage

scholarly journals A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice

2020 ◽  
Author(s):  
Anghesom Ghebremedhin ◽  
Ahmad Bin Salam ◽  
Benjamin Adu-Addai ◽  
Steve Noonan ◽  
Richard Stratton ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Early Stage ◽  
Blood Chemistry ◽  
Dependent Manner ◽  
Similar Reduction ◽  
Clinical Scenarios ◽  
Approved Drugs ◽  
Tgf Β1

AbstractActivated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNFα, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-β1 and α-SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNFα, IL-6, IL-10, INF-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

scholarly journals DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1593 ◽  
Author(s):  
Nicolas Malaquin ◽  
Arthur Vancayseele ◽  
Sophie Gilbert ◽  
Laureen Antenor-Habazac ◽  
Marc-Alexandre Olivier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Fate ◽  
Cancer Cell ◽  
Parp Inhibitors ◽  
Model Systems ◽  
Dependent Manner ◽  
Systematic Analysis ◽  
Context Dependent

Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.

scholarly journals NAD consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

2018 ◽  
Author(s):  
Michael M. Murata ◽  
Xiangduo Kong ◽  
Emmanuel Moncada ◽  
Yumay Chen ◽  
Ping Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Dna ◽  
Critical Role ◽  
Fluorescence Lifetime Imaging ◽  
Dependent Manner ◽  
Spatiotemporal Resolution ◽  
Parp Activation ◽  
Laser Microirradiation

AbstractDNA damage signaling is critical for the maintenance of genome integrity and cell fate decision. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor rapidly activated in a damage dose and complexity-dependent manner playing a critical role in the initial chromatin organization and DNA repair pathway choice at damage sites. However, the cell-wide consequence of its activation in damaged cells is not well delineated. Using the phasor approach to fluorescence lifetime imaging microscopy (FLIM) and fluorescence-based biosensors in combination with laser microirradiation, we found a rapid cell-wide increase of the bound/free NADH ratio in response to nuclear DNA damage, which is triggered by NAD+ depletion by PARP activation. This change is linked to the metabolic balance shift to oxidative phosphorylation (oxphos) over glycolysis. Inhibition of the respiratory chain resulted in rapid PARP-dependent ATP reduction and intracellular acidification, and eventually, PARP-dependent, AIF-independent, apoptosis indicating that oxphos becomes critical for damaged cell survival. The results reveal the novel pro-survival effect of PARP activation through a change in cellular metabolism, and demonstrate how unique applications of advanced fluorescence imaging technologies in combination with laser microirradiation can be a powerful tool to interrogate damage-induced metabolic changes at high spatiotemporal resolution in a live cell.

scholarly journals Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

2020 ◽  
Vol 21 (2) ◽  
pp. 643 ◽  
Author(s):  
Willy Roque ◽  
Karina Cuevas-Mora ◽  
Freddy Romero
Keyword(s):  
Dna Damage ◽  
Quality Control ◽  
Growth Factors ◽  
Pulmonary Fibrosis ◽  
Mitochondrial Biogenesis ◽  
Tissue Repair ◽  
Mitochondrial Protein ◽  
Unknown Etiology ◽  
Mitochondrial Quality Control ◽  
Age Related

Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.

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