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Cited by 271Autophagy in Disease and TherapyTelomeres, Telomerase, and SenescenceChronic Obstructive Pulmonary Disease (COPD) Research

Impaired mitophagy leads to cigarette smoke stress‐induced cellular senescence: implications for chronic obstructive pulmonary disease

Open access
Ahmad, Tanveer, Sundar, Isaac K., Lerner, Chad A., Gerloff, Janice, Tormos, Ana M., Yao, Hongwei, Rahman, Irfan·2015·The FASEB Journal
DOI 10.1096/fj.14-268276PMC PMC4478793
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Abstract

Cigarette smoke (CS)‐induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The molecular mechanism by which CS induces cellular senescence is unknown. Here, we show that CS stress (exposure of primary lung cells to CS extract 0.2‐0.75% with a half‐maximal inhibitory concentration of ~0.5%) led to impaired mitophagy and perinuclear accumulation of damaged mitochondria associated with cellular senescence in both human lung fibroblasts and small airway epithelial cells (SAECs). Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS‐induced cytoplasmic p53 accumulation and its interaction with Parkin. Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m 3 ) as well as in lungs of chronic smokers and patients with COPD. Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling. Mitochondria‐targeted antioxidant (Mito‐Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin‐overexpressing cells. In conclusion, defective mitophagy leads to CS stress‐induced lung cellular senescence, and restoring mitophagy delays cellular senescence, which provides a promising therapeutic intervention in chronic airway diseases.—Ahmad, T., Sundar, I. K., Lerner, C. A., Gerloff, J., Tormos, A. M., Yao, H., Rahman, I. Impaired mitophagy leads to cigarette smoke stress‐induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J . 29, 2912‐2929 (2015). www.fasebj.org

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Written from the paper’s full text.

TL;DR

Cigarette smoke stress impairs mitophagy in lung fibroblasts and small airway epithelial cells, leading to perinuclear accumulation of damaged mitochondria, DNA damage, and cellular senescence. Restoring Parkin-mediated mitophagy together with mitochondria-targeted antioxidant treatment delays senescence, suggesting a therapeutic target in COPD.

Key findings

  • CSE exposure (0.2–0.75%; half-maximal inhibitory concentration ∼0.5%) induced cellular senescence in human lung fibroblasts and SAECs, with increased SA-β-gal/C12FDG, p16, p21, γ-H2AX foci, mtROS, mitochondrial mass, and decreased ATP.
  • Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, linked to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin; Pink1 was stabilized on mitochondria, Mfn2 increased, and Drp1 showed more cytoplasmic localization with a slight decrease.
  • Impaired Parkin mitochondrial translocation was also seen in mouse lungs with emphysema after 6 months CS exposure (100 mg TPM/m3), in lungs of chronic smokers and patients with COPD, and in primary SAECs from patients with COPD, which showed increased mitochondrial mass and senescence augmented by CSE.
  • Parkin overexpression restored mitophagy and reduced mitochondrial mass; in Parkin-overexpressing cells, Mito-Tempo (1 µM) reduced mtROS, perinuclear mitochondrial accumulation, γ-H2AX foci, and delayed cellular senescence. MitoT alone reduced mtROS but did not rescue impaired mitophagy or senescence.

Methods

  • In vitro models used human lung fibroblasts (HFL1, WI-38 LC3-GFP), primary mouse lung fibroblasts, and human primary SAECs from nonsmokers and patients with COPD; CSE was used at 0.2–0.75%, with 0.5% for HFL1, 0.25% for mouse lung fibroblasts, and 0.2% for human SAECs, over 10–15 days with alternate-day treatment.
  • In vivo/ex vivo samples included 8-week-old C57BL/6J mice exposed to CS 5 h/day, 5 days/week for 6 months at ∼100 mg/m3 total particulate matter, and human lung tissue from normal nonsmokers, smokers, and patients with COPD.
  • Assays included SA-β-gal, C12FDG flow cytometry, immunofluorescence/confocal microscopy, electron microscopy, MitoTracker Green/Red, MitoSOX, TMRM, mitochondrial ATP, γ-H2AX foci, CellROX, Western blot, mitochondrial isolation, and 1-way ANOVA with means ± SEM.

Limitations

  • Stated: long-term nocodazole treatment caused cell death, so the effect of perinuclear mitochondrial accumulation on cellular senescence could not be directly evaluated; Parkin was transiently overexpressed while CSE treatment continued for 15 days; MitoT alone had no significant effect on senescence, possibly due to insufficient concentration/duration; further studies are needed with stable Parkin overexpression, Parkin knockout mice, in vivo MitoT, other lung cell types, and transmitophagy.
  • Evident from the text: much of the mechanistic evidence is in vitro, while human COPD/smoker data are tissue associations rather than causal in vivo experiments; mitophagy is assessed mainly by Parkin translocation and LC3 colocalization rather than direct flux measurements; no in vivo rescue with MitoT or Parkin is reported.

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Integrity signals

Registry

Crossref · 10.1096/fj.14-268276

Cites

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Claims the paper makes

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  • Findingown data
    § Abstract

    Mito-Tempo delayed cellular senescence in Parkin-overexpressing cells.

    “Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Primary small airway epithelial cells from patients with COPD exhibited increased cellular senescence.

    “Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Mito-Tempo decreased mitochondrial mass accumulation in Parkin-overexpressing cells.

    “Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells.”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS

    Cigarette smoke extract treatment increased nuclear reactive oxygen species.

    “Imaging studies revealed an increased nuclear ROS with CSE treatment, although most of the ROS showed a cytoplasmic localization in control untreated cells (Fig. 2G, H).”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS

    CCCP treatment could not induce LC3-GFP association with mitochondria in cells treated with a combination of rotenone and Mdivi-1.

    “CCCP (catalog number C2759; Sigma-Aldrich) treatment could not induce LC3-GFP association with mitochondria in cells treated with a combination of rotenone and Mdivi-1 (Fig. 4E, F).”
    Quote in the paperSubstantial claim
  • May combine two claims. 50
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data
    § RESULTS

    Bafilomycin treatment induced more mitochondrial fragmentation, and long-term bafilomycin treatment led to cell death rather than cellular senescence.

    “whereas bafilomycin treatment induced more mitochondria fragmentation, and long-term bafilomycin treatment led to cell death rather than cellular senescence (Supplemental Fig. S2G, J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Treatment of mouse lung fibroblasts with Mdivi-1 led to mitochondrial elongation, mitochondrial mass accumulation, and increased cellular senescence.

    “Treatment of cells with Mdivi-1 led to mitochondrial elongation, mitochondrial mass accumulation (Fig. 4A, B), and an increase in cellular senescence (Fig. 4C)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    CCCP treatment induced Parkin-dependent mitophagy in control cells but not in cigarette smoke extract-treated cells with cellular senescence.

    “Treatment of cells with CCCP induced a Parkin-dependent mitophagy, as evident by LC3-GFP colocalization in control cells, but not in CSE-treated cells with cellular senescence (Fig. 3G, H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Cigarette smoke extract treatment resulted in decreased mitochondrial membrane potential and increased stabilization of Pink1 on mitochondria.

    “CSE treatment resulted in a decrease in ΔΨm (Fig. 2A) and showed increased stabilization of Pink1 (catalog number 6946S; Cell Signaling Technology) on mitochondria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Cigarette smoke extract treatment increased mitochondrial mass and caused formation of highly elongated mitochondria in HFL1 cells.

    “Confocal microscopy imaging revealed an increase in mitochondrial mass and formation of highly elongated mitochondria after CSE treatment (Fig. 1G)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    During cigarette smoke extract treatment, mitochondrial mass accumulation, mitochondrial reactive oxygen species, mitochondrial membrane potential, and cellular senescence were closely correlated.

    “Time kinetic data revealed a close correlation among mitochondrial mass accumulation, mtROS, ΔΨm, and cellular senescence during CSE treatment (Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Cigarette smoke extract treatment increased Mfn2 levels and mitochondrial localization, and caused Drp1 to show more cytoplasmic localization, although slightly decreased.

    “Furthermore, levels of Mfn2 (catalog number 11925; Cell Signaling Technology), a mitochondrial fusion protein, were increased and showed more mitochondrial localization, whereas the mitochondrial fission protein dynamin-related protein-1 (Drp1; catalog number ab56788; Abcam) showed more cytoplasmic localization, although slightly decreased (Fig. 3A, B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    After 24 hours, cigarette smoke extract treatment induced robust perinuclear mitochondrial accumulation and increased mitochondrial reactive oxygen species particularly in the perinuclear region.

    “After 24 hours, CSE treatment induced a robust perinuclear mitochondrial accumulation (Fig. 2C, D), with increased mtROS, particularly in the perinuclear region (Fig. 2E, F).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § RESULTS

    Mitochondria become highly elongated and increase in mass during establishment of cellular senescence, and at earlier time points more mitochondria show perinuclear accumulation.

    “Immunofluorescence staining revealed that mitochondria become highly elongated during the establishment of cellular senescence and increase in mass (Fig. 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Impaired mitophagy is seen in both smokers and patients with COPD as well as in a mouse model of chronic cigarette smoke-induced emphysema.

    “Impaired mitophagy was also seen in both smokers and patients with COPD as well as in a mouse model of chronic CS-induced emphysema.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    In isolated mitochondria, CCCP treatment increased Parkin mitochondrial translocation in control cells, whereas CCCP-induced Parkin mitochondrial translocation was highly reduced in cigarette smoke extract-treated HFL1 cells.

    “In isolated mitochondria, CCCP (a known Parkin mitochondrial translocation agent) treatments resulted in increased Parkin mitochondrial translocation in control cells, whereas CCCP-induced Parkin mitochondrial translocation was highly reduced in CSE-treated HFL1 cells (Fig. 3E, F), indicating impaired mitophagy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    A combination of rotenone and Mdivi-1 induced robust mitochondrial elongation, increased mitochondrial mass, and cellular senescence.

    “Interestingly, a combination of rotenone and Mdivi-1 induced a robust mitochondrial elongation, increased mitochondrial mass, and cellular senescence (Fig. 4A–D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Rotenone resulted in increased mitochondrial reactive oxygen species, mitochondrial mass accumulation, and increased cellular senescence after 15 days of cigarette smoke extract treatment.

    “Rotenone resulted in increased mtROS (Supplemental Fig. S2K) and mitochondrial mass accumulation, as well as an increase in cellular senescence after 15 days of CSE treatment (Fig. 4A–D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Nocodazole treatment inhibited perinuclear mitochondrial accumulation and decreased gamma-H2AX foci formation after 24 hours in cigarette smoke extract-treated cells but caused cell death later.

    “We found that nocodazole treatment inhibited perinuclear mitochondrial accumulation (Supplemental Fig. S1C, D) and decreased γ-H2AX foci formation after 24 hours in CSE-treated cells (Supplemental Fig. S1E) but caused cell death later (Supplemental Fig. S1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Cigarette smoke extract treatment led to increased mitochondrial reactive oxygen species and decreased ATP levels in HFL1 cells with senescence.

    “Furthermore, CSE treatment led to increased mtROS and decreased ATP levels in HFL1 cells with senescence (Fig. 1E, F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Cigarette smoke extract treatment for 15 days induced increased cytosolic p53 levels and its association with Parkin, which was reduced by nocodazole treatment.

    “CSE treatment for 15 days induced increased cytosolic p53 levels and its association with Parkin, which was reduced by nocodazole treatment (Supplemental Fig. S2E, F, H, I).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Impaired Parkin translocation to mitochondria occurs in CS-exposed mouse lungs and in lungs of human smokers and patients with COPD.

    “Studies in the isolated mitochondria showed impaired Parkin translocation to mitochondria in CS-exposed mouse lungs, as well as in the lungs of human smokers and patients with COPD (Figs. 8E, F, and 9C, D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Parkin overexpression in HFL1 cells decreased mitochondrial mass accumulation but did not much change cellular senescence after 15 days of cigarette smoke extract treatment.

    “Furthermore, using Parkin overexpression in HFL1 cells, we observed a decrease in mitochondrial mass accumulation (Fig. 5G), but not much change in cellular senescence after 15 days of CSE treatment (Fig. 5H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    CSE treatment further augments mitochondrial mass and cellular senescence in human COPD SAECs.

    “Human COPD SAECs showed increased mitochondrial mass (Fig. 7A, B) and cellular senescence (Fig. 7C, D), which was further augmented by CSE treatment (Fig. 7A–D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Parkin overexpression restores mitochondrial mass accumulation but does not significantly impact cellular senescence when CS already establishes cellular senescence.

    “These results show that Parkin overexpression can restore mitochondrial mass accumulation but does not have a significant impact on cellular senescence when CS already establishes the cellular senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Parkin overexpression during cigarette smoke extract treatment restored mitophagy, decreased perinuclear mitochondrial accumulation, caused a slight decrease in gamma-H2AX foci formation, but did not much change mitochondrial reactive oxygen species levels.

    “Parkin overexpression during CSE treatment restored mitophagy, as shown by recruitment of Parkin to mitochondria (Fig. 5A–C), which resulted in decreased perinuclear mitochondrial accumulation (Fig. 5D), and a slight decrease in γ-H2AX foci formation, but not much change in mtROS levels (Fig. 5E, F, and Supplemental Fig. S3A, B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    Mdivi-1 or rotenone induced cellular senescence.

    “This is corroborated by our findings that either Mdivi-1 (mitophagy inhibitor) (49) or rotenone (increasing mtROS generation) (35) induced perinuclear accumulation of damaged mitochondria and cellular senescence.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Gomes L. C., Di Benedetto G., Scorrano L. (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [35] Ahmad T., Aggarwal K., Pattnaik B., Mukherjee S., Sethi T., Tiwari B. K., Kumar M., Micheal A., Mabalirajan U., Ghosh B., Sinha Roy S., Agrawal A. (2013) Computational classification of mitochondrial shapes reflects stress and redox state. Cell Death Dis. 4, e461 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § DISCUSSION

    In mice with emphysema, increased senescence markers were associated with defective mitophagy and decreased mitochondrial function.

    “This was associated with defective mitophagy and decreased mitochondrial function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    CSE treatment further augmented increased cellular senescence and decreased mitophagy in primary SAECs from patients with COPD.

    “Furthermore, primary SAECs from patients with COPD exhibited increased cellular senescence and decreased mitophagy, which was further augmented by CSE treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § DISCUSSION

    We observed increased mitochondrial fragmentation with high concentration of CSE treatment.

    “Although we have also observed increased mitochondrial fragmentation with high concentration of CSE treatment (data not shown), the objective of this study was to elucidate the role of mitochondrial quality control during cellular senescence (using low concentration of CSE treatment), which is one of the critical factors for COPD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Cigarette smoke leads to increased cellular senescence associated with increased reactive oxygen species production in lung cells.

    “We have recently shown that CS leads to increased cellular senescence associated with increased reactive oxygen species (ROS) production in lung cells (3, 6, 8).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Hwang J. W., Yao H., Caito S., Sundar I. K., Rahman I. (2013) Redox regulation of SIRT1 in inflammation and cellular senescence. Free Radic. Biol. Med. 61, 95–110 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [6] Yao H., Chung S., Hwang J. W., Rajendrasozhan S., Sundar I. K., Dean D. A., McBurney M. W., Guarente L., Gu W., Rönty M., Kinnula V. L., Rahman I. (2012) SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J. Clin. Invest. 122, 2032–2045 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [8] Yao H., Sundar I. K., Ahmad T., Lerner C., Gerloff J., Friedman A. E., Phipps R. P., Sime P. J., McBurney M. W., Guarente L., Rahman I. (2014) SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L816–L828 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Once recruited to mitochondria, Parkin mediates degradation of mitofusin-2 and prevents mitochondrial fusion.

    “Once recruited to mitochondria, Parkin mediates degradation of mitofusin-2 (Mfn2; a core protein involved in mitochondrial fusion) and hence prevents mitochondrial fusion.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Yamano K., Fogel A. I., Wang C., van der Bliek A. M., Youle R. J. (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [21] Chen Y., Dorn G. W. II (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Mitophagy is activated by mitochondrial membrane depolarization, followed by stabilization of Pink1 on the mitochondrial outer membrane, which recruits Parkin from the cytosol.

    “Mitophagy is activated by mitochondrial membrane depolarization, followed by stabilization of a phosphatase and tensin homolog-induced putative kinase 1 (Pink1) on mitochondrial outer membrane, which then recruits an E3 ubiquitin ligase (Parkin) from the cytosol (17–19).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Youle R. J., Narendra D. P. (2011) Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [18] Bingol B., Tea J. S., Phu L., Reichelt M., Bakalarski C. E., Song Q., Foreman O., Kirkpatrick D. S., Sheng M. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [19] Vincow E. S., Merrihew G., Thomas R. E., Shulman N. J., Beyer R. P., MacCoss M. J., Pallanck L. J. (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl. Acad. Sci. USA 110, 6400–6405 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Cellular senescence is characterized by activation of p16, p21, and p53, along with increased senescence-associated beta-galactosidase activity.

    “Cellular senescence is characterized by the activation of p16, p21, and p53, along with increased activity of senescence-associated β-galactosidase (SA-β-gal) (6, 7).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Yao H., Chung S., Hwang J. W., Rajendrasozhan S., Sundar I. K., Dean D. A., McBurney M. W., Guarente L., Gu W., Rönty M., Kinnula V. L., Rahman I. (2012) SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J. Clin. Invest. 122, 2032–2045 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [7] Rodier F., Campisi J. (2011) Four faces of cellular senescence. J. Cell Biol. 192, 547–556 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Mitochondrial structural changes or dysfunction are induced by cigarette smoke stress.

    “This suggests that mitochondrial structural changes or its dysfunction is induced by CS stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Mitochondrial fission highly correlates with cell apoptosis and mitophagy, whereas mitochondrial fusion has the opposite role.

    “Mitochondrial fission highly correlates with cell apoptosis and mitophagy (selective degradation of damaged mitochondria), whereas mitochondrial fusion has the opposite role (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Youle R. J., van der Bliek A. M. (2012) Mitochondrial fission, fusion, and stress. Science 337, 1062–1065 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Elongated mitochondria with increased mitochondrial fusion activity occur during long-term cigarette smoke extract treatment in a human lung epithelial cell line.

    “Similarly, elongated mitochondria with increased mitochondrial fusion activity occur during long-term CSE treatment in a human lung epithelial cell line (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Hoffmann R. F., Zarrintan S., Brandenburg S. M., Kol A., de Bruin H. G., Jafari S., Dijk F., Kalicharan D., Kelders M., Gosker H. R., Ten Hacken N. H., van der Want J. J., van Oosterhout A. J., Heijink I. H. (2013) Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14, 97 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Cigarette smoke extract induces mitochondrial fission in human smooth muscle cells, which may contribute to cell death during COPD/emphysema pathogenesis.

    “Cigarette smoke extract (CSE) induces mitochondrial fission in human smooth muscle cells, which may contribute to cell death during the pathogenesis of COPD/emphysema (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Aravamudan B., Kiel A., Freeman M., Delmotte P., Thompson M., Vassallo R., Sieck G. C., Pabelick C. M., Prakash Y. S. (2014) Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L840–L854 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Damaged or dysfunctional mitochondria are cleared from cells by mitophagy.

    “Damaged or dysfunctional mitochondria are cleared from the cells by a process called mitophagy (16–18).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Ashrafi G., Schwarz T. L. (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [17] Youle R. J., Narendra D. P. (2011) Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [18] Bingol B., Tea J. S., Phu L., Reichelt M., Bakalarski C. E., Song Q., Foreman O., Kirkpatrick D. S., Sheng M. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Autophagosomes containing damaged mitochondria fuse with lysosomes and are cleared from cells.

    “These autophagosomes containing the damaged mitochondria fuse with lysosomes which are cleared from the cells (16–21).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [16] Ashrafi G., Schwarz T. L. (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [17] Youle R. J., Narendra D. P. (2011) Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [18] Bingol B., Tea J. S., Phu L., Reichelt M., Bakalarski C. E., Song Q., Foreman O., Kirkpatrick D. S., Sheng M. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [19] Vincow E. S., Merrihew G., Thomas R. E., Shulman N. J., Beyer R. P., MacCoss M. J., Pallanck L. J. (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl. Acad. Sci. USA 110, 6400–6405 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [20] Yamano K., Fogel A. I., Wang C., van der Bliek A. M., Youle R. J. (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [21] Chen Y., Dorn G. W. II (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Defective mitophagy is linked with premature aging and age-associated disorders such as Alzheimer's and Parkinson's diseases.

    “Defective mitophagy has also been linked with premature aging and many age-associated disorders, such as Alzheimer’s and Parkinson’s diseases (25–28).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [25] Chistiakov D. A., Sobenin I. A., Revin V. V., Orekhov A. N., Bobryshev Y. V. (2014) Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res. Int. 2014, 238463. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [26] Bratic A., Larsson N. G. (2013) The role of mitochondria in aging. J. Clin. Invest. 123, 951–957 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [27] Hoshino A., Mita Y., Okawa Y., Ariyoshi M., Iwai-Kanai E., Ueyama T., Ikeda K., Ogata T., Matoba S. (2013) Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4, 2308 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [28] Bernhardt D., Müller M., Reichert A. S., Osiewacz H. D. (2015) Simultaneous impairment of mitochondrial fission and fusion reduces mitophagy and shortens replicative lifespan. Sci. Rep. 5, 7885 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Parkin recruitment initiates localization of damaged mitochondria to LC3-containing membranes, leading to autophagosome formation.

    “This initiates the localization of damaged mitochondria to membranes containing microtubule-associated protein light-chain 3 (LC3) leading to the formation of autophagosomes (20, 21).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Yamano K., Fogel A. I., Wang C., van der Bliek A. M., Youle R. J. (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3, e01612 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [21] Chen Y., Dorn G. W. II (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    During earlier time points, cigarette smoke extract stress results in increased perinuclear mitochondrial clustering, which may be the mechanism whereby dysfunctional mitochondria trigger cellular senescence.

    “Furthermore, during earlier time points, CSE stress results in increased perinuclear mitochondrial clustering, which may be the mechanism whereby dysfunctional mitochondria trigger the cellular senescence process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Cigarette smoke impairs mitophagy, which is associated with reduced Parkin mitochondrial translocation via p53.

    “Overall, CS impairs mitophagy, which is associated with reduced Parkin mitochondrial translocation via p53.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Accumulation of damaged or dysfunctional mitochondria due to impaired mitophagy is associated with many pathologic conditions.

    “Accumulation of damaged or dysfunctional mitochondria, due to impaired mitophagy, has been associated with many pathologic conditions (22–24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Osellame L. D., Duchen M. R. (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9, 1633–1635 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [23] Heeman B., Van den Haute C., Aelvoet S. A., Valsecchi F., Rodenburg R. J., Reumers V., Debyser Z., Callewaert G., Koopman W. J., Willems P. H., Baekelandt V. (2011) Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J. Cell Sci. 124, 1115–1125 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [24] Fang E. F., Scheibye-Knudsen M., Brace L. E., Kassahun H., SenGupta T., Nilsen H., Mitchell J. R., Croteau D. L., Bohr V. A. (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882–896 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Cigarette smoke extract treatments lead to mitochondrial dysfunction, and mitochondria become highly interconnected and accumulated in senescent cells.

    “From these results, we infer that CSE treatments lead to mitochondrial dysfunction, and mitochondria become highly interconnected and accumulated in senescent cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Restoring mitophagy and attenuating mtROS can prevent the progression of cellular senescence in primary lung fibroblasts.

    “These results show that restoring mitophagy and attenuating mtROS can prevent the progression of cellular senescence in primary lung fibroblasts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Mitophagy is highly impaired during CS exposure in mouse lungs and in lungs of smokers and patients with COPD.

    “These results provide evidence that mitophagy is highly impaired during CS exposure in mouse lungs as well as in the lungs of smokers and patients with COPD, which may be a contributing factor for cellular senescence during the pathogenesis of COPD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § MATERIALS AND METHODS

    A Mito-Tempo dose of 1 micromolar that induced substantial reduction in mitochondrial reactive oxygen species was used for further experiments.

    “Mito-Tempo (MitoT) was used at different concentrations (100 nM, 500 nM, 1 µM, and 2 µM), and a dose (1 µM) that induced substantial reduction in mitochondrial reactive oxygen species (mtROS) was used for further experiments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    The study demonstrates a previously unknown molecular pathway for CS stress-induced cellular senescence via mitochondrial dysfunction in vitro in human lung fibroblasts and human primary SAECs, and in vivo in mouse lungs as well as ex vivo in the lungs of patients with COPD.

    “We have shown here a previously unknown molecular pathway for CS stress-induced cellular senescence via mitochondrial dysfunction in vitro in human lung fibroblasts and human primary SAECs, and in vivo in mouse lungs as well as ex vivo in the lungs of patients with COPD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § RESULTS

    Human COPD and smoker lungs are associated with increased p16 and p21 levels, as well as SA-β-gal activity.

    “We have also previously shown that human COPD and smoker lungs are associated with increased p16 and p21 levels, as well as SA-β-gal activity (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Yao H., Chung S., Hwang J. W., Rajendrasozhan S., Sundar I. K., Dean D. A., McBurney M. W., Guarente L., Gu W., Rönty M., Kinnula V. L., Rahman I. (2012) SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J. Clin. Invest. 122, 2032–2045 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § MATERIALS AND METHODS

    The cigarette smoke extract dose was chosen on the basis of a dose-response curve to induce substantial cellular senescence with minimal apoptosis over 10 or 15 days of alternate-day treatment.

    “The dose of CSE was chosen on the basis of dose response curve generated, which induced substantial cellular senescence with minimal apoptosis for a period of 10 or 15 days with alternate days of CSE treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Parkin overexpression delays aging in flies.

    “Parkin overexpression is shown to delay aging in flies (47, 48).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Ballweg K., Mutze K., Königshoff M., Eickelberg O., Meiners S. (2014) Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L895–L907 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [48] Hara H., Araya J., Ito S., Kobayashi K., Takasaka N., Yoshii Y., Wakui H., Kojima J., Shimizu K., Numata T., Kawaishi M., Kamiya N., Odaka M., Morikawa T., Kaneko Y., Nakayama K., Kuwano K. (2013) Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L737–L746 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION

    Parkin overexpression has been shown to increase the life span in flies and reduces oxidative stress by activating mitophagy.

    “Parkin overexpression has been shown to increase the life span in flies and reduces oxidative stress by activating mitophagy (50, 51).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Rana A., Rera M., Walker D. W. (2013) Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc. Natl. Acad. Sci. USA 110, 8638–8643 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [51] Saini N., Georgiev O., Schaffner W. (2011) The parkin mutant phenotype in the fly is largely rescued by metal-responsive transcription factor (MTF-1). Mol. Cell. Biol. 31, 2151–2161 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § DISCUSSION

    Increased p53 cytosolic localization prevents Parkin translocation to mitochondria during organismal aging.

    “A recent study has shown that increased p53 cytosolic localization prevents Parkin translocation to mitochondria during organismal aging (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Hoshino A., Mita Y., Okawa Y., Ariyoshi M., Iwai-Kanai E., Ueyama T., Ikeda K., Ogata T., Matoba S. (2013) Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4, 2308 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    CS causes mitophagy impairment and mtROS generation, which may drive DNA damage and cellular senescence.

    “Therefore, CS causes mitophagy impairment and mtROS generation, which may drive DNA damage and cellular senescence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    mtROS inhibitor reduces senescence in bone marrow mesenchymal stem cells.

    “mtROS has been shown as a key inducer for premature aging, and mtROS inhibitor reduces senescence in bone marrow mesenchymal stem cells (52, 53).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Wu J., Niu J., Li X., Wang X., Guo Z., Zhang F. (2014) TGF-β1 induces senescence of bone marrow mesenchymal stem cells via increase of mitochondrial ROS production. BMC Dev. Biol. 14, 21 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [53] Tao R., Vassilopoulos A., Parisiadou L., Yan Y., Gius D. (2014) Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid. Redox Signal. 20, 1646–1654 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    Cytosolic translocation of p53 was partly mediated by perinuclear mitochondrial accumulation, followed by DNA damage foci formation.

    “This indicates that cytosolic translocation of p53 was partly mediated by perinuclear mitochondrial accumulation, followed by DNA damage foci formation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § DISCUSSION

    The lack of significant effect of MitoT alone on cellular senescence may be due to insufficient concentration and duration used.

    “It is interesting to note that MitoT treatment alone did not show any significant effect on cellular senescence, which may be due to its insufficient concentration and duration used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    Both mitophagy impairment and mtROS generation contribute to CS-induced cellular senescence.

    “Altogether, both mitophagy impairment and mtROS generation contribute to CS-induced cellular senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    Both Pink1 and Parkin knockout mice exhibit increased ROS levels and mitochondrial dysfunction.

    “Both Pink1 and Parkin knockout mice exhibit increased ROS levels and mitochondrial dysfunction (43, 44), and persistent increased ROS is one of the important factors in accelerating cellular senescence (42, 45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Palacino J. J., Sagi D., Goldberg M. S., Krauss S., Motz C., Wacker M., Klose J., Shen J. (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614–18622 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [44] Haque M. E., Mount M. P., Safarpour F., Abdel-Messih E., Callaghan S., Mazerolle C., Kitada T., Slack R. S., Wallace V., Shen J., Anisman H., Park D. S. (2012) Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J. Biol. Chem. 287, 23162–23170 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § DISCUSSION

    Long-term nocodazole treatment led to cell death, preventing direct evaluation of the effect of perinuclear mitochondrial accumulation on cellular senescence.

    “Although long-term nocodazole treatment led to cell death, we were therefore unable to directly evaluate the effect of perinuclear mitochondrial accumulation on cellular senescence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § DISCUSSION

    Parkin is a core mitophagy-regulating protein, which is recruited to damaged or depolarized mitochondria to induce mitochondrial clearance.

    “Parkin is a core mitophagy-regulating protein, which is recruited to damaged or depolarized mitochondria to induce mitochondrial clearance (16–19).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Ashrafi G., Schwarz T. L. (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [17] Youle R. J., Narendra D. P. (2011) Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [18] Bingol B., Tea J. S., Phu L., Reichelt M., Bakalarski C. E., Song Q., Foreman O., Kirkpatrick D. S., Sheng M. (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [19] Vincow E. S., Merrihew G., Thomas R. E., Shulman N. J., Beyer R. P., MacCoss M. J., Pallanck L. J. (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl. Acad. Sci. USA 110, 6400–6405 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Mitochondria were highly fragmented in CS-exposed mouse lung epithelial cells.

    “A recent study has shown increased mitophagy with acute CSE treatment in cultured lung epithelial cells, whereas mitochondria were highly fragmented in CS-exposed mouse lung epithelial cells (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Mizumura K., Cloonan S. M., Nakahira K., Bhashyam A. R., Cervo M., Kitada T., Glass K., Owen C. A., Mahmood A., Washko G. R., Hashimoto S., Ryter S. W., Choi A. M. (2014) Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Acute CSE treatment increases mitophagy in cultured lung epithelial cells.

    “A recent study has shown increased mitophagy with acute CSE treatment in cultured lung epithelial cells, whereas mitochondria were highly fragmented in CS-exposed mouse lung epithelial cells (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Mizumura K., Cloonan S. M., Nakahira K., Bhashyam A. R., Cervo M., Kitada T., Glass K., Owen C. A., Mahmood A., Washko G. R., Hashimoto S., Ryter S. W., Choi A. M. (2014) Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    Defective mitophagy leads to accumulation of dysfunctional and damaged mitochondria and, hence, augmented cellular senescence during CS exposure in vitro in lung epithelial cells and fibroblasts, mouse lungs, as well as human smokers and patients with COPD.

    “In summary, we show here for the first time that the mechanisms of defective mitophagy lead to accumulation of dysfunctional and damaged mitochondria and, hence, augmented cellular senescence during CS exposure in vitro in lung epithelial cells and fibroblasts, mouse lungs, as well as human smokers and patients with COPD (Fig. 10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    This is associated with a reduction of Parkin-mediated mitophagy and an increase in mtROS-induced DNA damage.

    “This is associated with a reduction of Parkin-mediated mitophagy and an increase in mtROS-induced DNA damage.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Elongated mitochondria with increased mitochondrial fusion activity occur during long-term CSE treatment in a human lung epithelial cell line.

    “There is a study showing elongated mitochondria with increased mitochondrial fusion activity during long-term CSE treatment in a human lung epithelial cell line (15), which is in agreement with our findings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Hoffmann R. F., Zarrintan S., Brandenburg S. M., Kol A., de Bruin H. G., Jafari S., Dijk F., Kalicharan D., Kelders M., Gosker H. R., Ten Hacken N. H., van der Want J. J., van Oosterhout A. J., Heijink I. H. (2013) Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14, 97 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § DISCUSSION

    The discrepancies among studies on CSE and mitochondrial structural changes may be due to different cell culture conditions and the concentration and duration of CSE used.

    “The discrepancies among these studies may be due to different cell culture conditions and the concentration and duration of CSE used (14, 15, 48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Aravamudan B., Kiel A., Freeman M., Delmotte P., Thompson M., Vassallo R., Sieck G. C., Pabelick C. M., Prakash Y. S. (2014) Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L840–L854 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [15] Hoffmann R. F., Zarrintan S., Brandenburg S. M., Kol A., de Bruin H. G., Jafari S., Dijk F., Kalicharan D., Kelders M., Gosker H. R., Ten Hacken N. H., van der Want J. J., van Oosterhout A. J., Heijink I. H. (2013) Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14, 97 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [48] Hara H., Araya J., Ito S., Kobayashi K., Takasaka N., Yoshii Y., Wakui H., Kojima J., Shimizu K., Numata T., Kawaishi M., Kamiya N., Odaka M., Morikawa T., Kaneko Y., Nakayama K., Kuwano K. (2013) Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L737–L746 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Decreased expression of Drp1 and mitochondrial fission 1 protein induces cellular senescence via a Pink1-dependent manner.

    “Pink1 deficiency leads to mitochondrial damage and hence promotes lung fibrosis (56), whereas a decreased expression of mitochondrial fission proteins Drp1 and mitochondrial fission 1 protein induces cellular senescence via a Pink1-dependent manner (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Mai S., Klinkenberg M., Auburger G., Bereiter-Hahn J., Jendrach M. (2010) Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J. Cell Sci. 123, 917–926 [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION

    Pink1 deficiency leads to mitochondrial damage and hence promotes lung fibrosis.

    “Pink1 deficiency leads to mitochondrial damage and hence promotes lung fibrosis (56), whereas a decreased expression of mitochondrial fission proteins Drp1 and mitochondrial fission 1 protein induces cellular senescence via a Pink1-dependent manner (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Bueno M., Lai Y. C., Romero Y., Brands J., St Croix C. M., Kamga C., Corey C., Herazo-Maya J. D., Sembrat J., Lee J. S., Duncan S. R., Rojas M., Shiva S., Chu C. T., Mora A. L. (2015) PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Invest. 125, 521–538 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § DISCUSSION

    These findings unravel new insights into the molecular mechanisms of mitophagy regulating cellular senescence during CS stress-induced lung pathophysiologic responses.

    “Overall, these findings unravel new insights into the molecular mechanisms of mitophagy regulating cellular senescence during CS stress-induced lung pathophysiologic responses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Smooth muscle and transformed lung epithelial cells are equally sensitive to CS-induced cellular senescence.

    “Recent studies have also shown that smooth muscle and transformed lung epithelial cells are equally sensitive to CS-induced cellular senescence (14, 15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Aravamudan B., Kiel A., Freeman M., Delmotte P., Thompson M., Vassallo R., Sieck G. C., Pabelick C. M., Prakash Y. S. (2014) Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L840–L854 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [15] Hoffmann R. F., Zarrintan S., Brandenburg S. M., Kol A., de Bruin H. G., Jafari S., Dijk F., Kalicharan D., Kelders M., Gosker H. R., Ten Hacken N. H., van der Want J. J., van Oosterhout A. J., Heijink I. H. (2013) Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14, 97 [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

68 of 68

  • The paper relies on this without support.

    The molecular mechanism by which cigarette smoke induces cellular senescence is unknown.

    “However, the molecular mechanism by which CS induces cellular senescence is unknown.”

  • The paper relies on this without support.

    It is not clear whether cigarette smoke stress-induced lung cellular senescence is due to mitochondrial dysfunction via defective mitophagy.

    “However, it is not clear whether CS stress-induced lung cellular senescence is due to mitochondrial dysfunction via defective mitophagy.”

  • The paper relies on this without support.

    The molecular mechanism underlying cigarette smoke-induced mitochondrial structural changes or dysfunction and their impact during cellular senescence is not known.

    “However, the molecular mechanism underlying these phenomena and their impact during cellular senescence is not known.”

  • The paper relies on this without support.

    Most cellular reactive oxygen species are predominantly generated by mitochondria.

    “Most of the cellular ROS are predominantly generated by mitochondria”

  • The paper relies on this without support.

    The mechanisms and signaling pathways associated with CS stress-induced cellular senescence and COPD are not known.

    “Although a well-appreciated phenomenon, the mechanisms and the signaling pathways associated with CS stress-induced cellular senescence and COPD per se are not known.”

  • The paper relies on this without support.

    One of the major contributing factors of CS-induced COPD is oxidative stress.

    “One of the major contributing factors of CS-induced COPD is oxidative stress.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inhibition of mitophagy associated with genetic deletion of Prkn worsens the effect of CS by promoting entry of epithelial alveolar cells into senescence.

    “Nonetheless, the inhibition of mitophagy associated with the genetic deletion of Prkn worsen the effect of CS, as it promotes the entry of epithelial alveolar cells in the senescent state (Ahmad et al, 2015).”

    From Autophagy in major human diseases (2021) · cites this paper as Ahmad et al, 2015

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting bafilomycin treatment durations

    Minor

    The methods first include bafilomycin among treatments given for 15 days, then state that bafilomycin was used for 10 days.

1 of 1

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Authors
Ahmad, T., Sundar, I. K., Lerner, C. A., Gerloff, J., Tormos, A. M., Yao, H., & Rahman, I.
Affiliations
University of Rochester Medicine (US)
Corresponding author
  • Yao, Hongwei
  • Rahman, Irfan
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2015-03-19
Volume
29
Issue
7
Pages
2912-2929
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.14-268276
PMC
PMC4478793
OpenAlex
W2169986172
Semantic Scholar
5b955ac0453445e460563db134eebe8e6445cc9b
Cited by
264
References
60
Citations by year
2026: 13 · 2025: 17 · 2024: 17 · 2023: 33 · 2022: 30 · 2021: 35 · 2020: 25 · 2019: 22 · 2018: 25 · 2017: 25 · 2016: 16 · 2015: 6
FWCI
18.74
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (P30‐ES01247)
  • National Heart, Lung, and Blood Institute (2R01HL085613, 1R01HL092842)
  • American Lung Association (RG‐266456‐N, RG‐305393)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
cigarette smoke, cellular senescence, mitophagy, chronic obstructive pulmonary disease, Parkin, p53, mitochondrial damage, small airway epithelial cells, lung fibroblasts, emphysema, MitoTEMPO, subcellular signaling, mitochondrial quality control
MeSH terms
Animals, Antioxidants, Cells, Cultured, DNA Damage, Fibroblasts, Humans, Lung, Mice, Inbred C57BL, Organophosphorus Compounds, Piperidines, Smoking, Case-Control Studies, Cellular Senescence, Reactive Oxygen Species, Respiratory Mucosa, Pulmonary Disease, Chronic Obstructive, Ubiquitin-Protein Ligases, Mice, Mitophagy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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