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

In the paper

“Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells.”

In the paper

“Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling.”

In the paper

“Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells.”

In the paper

“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).”

In the paper

“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).”

In the paper

“We show that CSE causes persistent mitochondrial dysfunction leading to defective mitophagy by altering Parkin levels and translocation.”

In the paper

“However, Parkin (catalog number 2132S; Cell Signaling Technology) mitochondrial translocation was highly impaired in HFL1 cells by CSE (Fig. 3A, B).”

In the paper

“Our results show increased p16 and p21 levels (Fig. 1C)”

In the paper

“Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m3) as well as in lungs of chronic smokers and patients with COPD.”

In the paper

“A time-dependent increase in cellular senescence was observed in HFL1 and mouse primary lung fibroblasts, which was characterized by increased SA-β-gal activity (Fig. 1A and Supplemental Fig. S1A, B).”

In the paper

“CSE-induced perinuclear mitochondrial accumulation was associated with increased γ-H2AX foci formation, and a close correlation between the 2 was observed (Fig. 2I).”

In the paper

“An additive effect of rotenone and Mdivi-1 was also evident on LC3-GFP, which showed a reduced colocalization with mitochondria, indicating impaired mitophagy.”

In the paper

“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).”

In the paper

“Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m3) as well as in lungs of chronic smokers and patients with COPD.”

In the paper

“Furthermore, long-term CSE treatment was associated with accumulation of damaged mitochondria, which would have repercussions on mitophagy.”

In the paper

“we found that elongated mitochondria were mostly present in highly senescent cells after CSE treatment for 15 days (Fig. 1I).”

In the paper

“Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling.”

In the paper

“Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells.”

In the paper

“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).”

In the paper

“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).”

In the paper

“Parkin levels were not significantly changed in the whole-cell extracts between control and CSE-treated cells (Fig. 3B).”

In the paper

“as well as DNA damage, measured in terms of γ-H2AX foci formation”

In the paper

“mitochondrial localization to autophagosomes was highly impaired in CSE-treated human LC3-GFP-expressing fibroblast cells, as reflected by decreased mitochondrial localization to LC3-GFP (Supplemental Fig. S2A).”

In the paper

“Immunofluorescence results revealed increased expression of Pink1, whereas Parkin levels were decreased in both alveolar and bronchial epithelial cells in mice during chronic CS exposure (Fig. 8G–J).”

In the paper

“MitoT treatment resulted in a slight but insignificant decrease in perinuclear mitochondrial accumulation (Fig. 6A), mitochondrial mass (Fig. 6B), and DNA damage foci (reflected by γH2AX foci) formation (Fig. 6C).”

In the paper

“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).”

In the paper

“Long-term CSE-treated cells show increased mtROS and mitochondrial mass accumulation as well as mitophagy impairment.”

In the paper

“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).”

In the paper

“Furthermore, MitoT along with Parkin overexpression reduced γ-H2AX foci formation, mitochondrial mass accumulation, and mtROS along with partial reduction in cellular senescence after 15 days of CSE treatment (Fig. 7G–I and Supplemental Fig. S3C).”

In the paper

“CS-exposed mice lungs showed increased levels of Pink1, whereas Parkin expression did not show any differences (Fig. 8C, D).”

In the paper

“At earlier time points, CSE treatment was associated with increased perinuclear mitochondrial accumulation, which was highly correlated with the DNA damage foci formation.”

In the paper

“However, MitoT treatment could not restore impaired mitophagy (Fig. 6A, B).”

In the paper

“Furthermore, MitoT along with Parkin overexpression reduced γ-H2AX foci formation, mitochondrial mass accumulation, and mtROS along with partial reduction in cellular senescence after 15 days of CSE treatment (Fig. 7G–I and Supplemental Fig. S3C).”

In the paper

“We first developed a cell culture model of CSE stress-induced cellular senescence, where we showed that CSE treatment induced mitochondrial dysfunction and increased mtROS.”

In the paper

“Moreover, Parkin overexpression along with MitoT significantly reduced mitochondrial mass (Fig. 6B), DNA foci formation (Fig. 6C), and cellular senescence (Fig. 6D).”

In the paper

“CS-exposed mice lungs showed increased levels of Pink1, whereas Parkin expression did not show any differences (Fig. 8C, D).”

In the paper

“MitoT treatment led to mtROS reduction in CSE-treated cells (Supplemental Fig. S3A, B).”

In the paper

“MitoT treatment resulted in a slight but insignificant decrease in perinuclear mitochondrial accumulation (Fig. 6A), mitochondrial mass (Fig. 6B), and DNA damage foci (reflected by γH2AX foci) formation (Fig. 6C).”

In the paper

“As expected, MitoT reduced mtROS levels (Supplemental Fig. S3B) and decreased perinuclear mitochondrial accumulation in Parkin-overexpressing cells (Fig. 6A).”

In the paper

“There was also a slight decrease in cellular senescence after MitoT treatment (Fig. 6D).”

In the paper

“Consistent with our previous studies (6), increased p16 and p21 levels were seen in mouse lung structural cells after 6 mo of CS exposure (Fig. 8A, B).”

What the sources say

• Not checked yetcites [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

In the paper

“As expected, MitoT reduced mtROS levels (Supplemental Fig. S3B) and decreased perinuclear mitochondrial accumulation in Parkin-overexpressing cells (Fig. 6A).”

In the paper

“We first developed a cell culture model of CSE stress-induced cellular senescence, where we showed that CSE treatment induced mitochondrial dysfunction and increased mtROS.”

In the paper

“Immunofluorescence results revealed increased expression of Pink1, whereas Parkin levels were decreased in both alveolar and bronchial epithelial cells in mice during chronic CS exposure (Fig. 8G–J).”

In the paper

“MitoT treatment resulted in a slight but insignificant decrease in perinuclear mitochondrial accumulation (Fig. 6A), mitochondrial mass (Fig. 6B), and DNA damage foci (reflected by γH2AX foci) formation (Fig. 6C).”

In the paper

“Moreover, Parkin overexpression along with MitoT significantly reduced mitochondrial mass (Fig. 6B), DNA foci formation (Fig. 6C), and cellular senescence (Fig. 6D).”

In the paper

“SAECs from patients with COPD also displayed reduced Parkin mitochondrial translocation in the presence of CCCP compared to cells from normal subjects, implicating impaired mitophagy (Fig. 7E, F).”

In the paper

“At earlier time points, CSE treatment was associated with increased perinuclear mitochondrial accumulation, which was highly correlated with the DNA damage foci formation.”

In the paper

“Long-term CSE-treated cells show increased mtROS and mitochondrial mass accumulation as well as mitophagy impairment.”

In the paper

“Furthermore, MitoT along with Parkin overexpression reduced γ-H2AX foci formation, mitochondrial mass accumulation, and mtROS along with partial reduction in cellular senescence after 15 days of CSE treatment (Fig. 7G–I and Supplemental Fig. S3C).”

In the paper

“Moreover, Parkin overexpression along with MitoT significantly reduced mitochondrial mass (Fig. 6B), DNA foci formation (Fig. 6C), and cellular senescence (Fig. 6D).”

In the paper

“Long-term CSE-treated cells show increased mtROS and mitochondrial mass accumulation as well as mitophagy impairment.”

In the paper

“Furthermore, MitoT along with Parkin overexpression reduced γ-H2AX foci formation, mitochondrial mass accumulation, and mtROS along with partial reduction in cellular senescence after 15 days of CSE treatment (Fig. 7G–I and Supplemental Fig. S3C).”

In the paper

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

In the paper

“Parkin overexpression also reduced mitochondrial mass accumulation as well as caused a slight decrease in γ-H2AX foci formation and cellular senescence.”

In the paper

“We found that Parkin overexpression restored mitophagy in CSE-treated cells.”

In the paper

“Interestingly, Parkin-overexpressing cells treated with MitoT showed a significant decrease in DNA damage foci formation, perinuclear mitochondrial accumulation, mtROS, and delayed cellular senescence.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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
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In the paper

“Parkin overexpression also reduced mitochondrial mass accumulation as well as caused a slight decrease in γ-H2AX foci formation and cellular senescence.”

In the paper

“Inhibition of perinuclear mitochondrial accumulation by nocodazole decreased DNA damage/γH2AX foci, p53 cytosolic levels, and p53’s association with Parkin in response to CSE treatment.”

In the paper

“Interestingly, Parkin-overexpressing cells treated with MitoT showed a significant decrease in DNA damage foci formation, perinuclear mitochondrial accumulation, mtROS, and delayed cellular senescence.”

In the paper

“Additionally, p53 interaction with Parkin was highly increased during CSE-induced cellular senescence.”

In the paper

“Inhibition of perinuclear mitochondrial accumulation by nocodazole decreased DNA damage/γH2AX foci, p53 cytosolic levels, and p53’s association with Parkin in response to CSE treatment.”

In the paper

“Inhibition of perinuclear mitochondrial accumulation by nocodazole decreased DNA damage/γH2AX foci, p53 cytosolic levels, and p53’s association with Parkin in response to CSE treatment.”

In the paper

“Parkin overexpression also reduced mitochondrial mass accumulation as well as caused a slight decrease in γ-H2AX foci formation and cellular senescence.”

In the paper

“Chronic CSE treatment induced mitochondrial elongation, which prevented mitochondrial clearance via mitophagy.”

In the paper

“In our study, although the total Parkin levels were not significantly altered between control and CSE-treated cells, CCCP-mediated Parkin translocation to mitochondria was reduced by CSE, suggesting impaired clearance of damaged mitochondria.”

In the paper

“Similarly, the lungs from both patients with COPD and smokers exhibited defective mitophagy.”

In the paper

“Chronic CSE treatment induced mitochondrial elongation, which prevented mitochondrial clearance via mitophagy.”

In the paper

“In our study, although the total Parkin levels were not significantly altered between control and CSE-treated cells, CCCP-mediated Parkin translocation to mitochondria was reduced by CSE, suggesting impaired clearance of damaged mitochondria.”

In the paper

“Interestingly, Parkin-overexpressing cells treated with MitoT showed a significant decrease in DNA damage foci formation, perinuclear mitochondrial accumulation, mtROS, and delayed cellular senescence.”

In the paper

“We found increased p53 expression in the cytoplasm with CSE treatment.”

In the paper

“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.”

In the paper

“Interestingly, Parkin-overexpressing cells treated with MitoT showed a significant decrease in DNA damage foci formation, perinuclear mitochondrial accumulation, mtROS, and delayed cellular senescence.”

In the paper

“Second, Parkin overexpression did not have any effect on mtROS levels, which is one of the important factors in inducing cellular senescence.”

In the paper

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

In the paper

“We showed increased translocation of Pink1, but not Drp1, into mitochondria in CSE-treated cells, CS-exposed mouse lung with emphysema, and the lung of patients with COPD.”

In the paper

“Parkin overexpression along with MitoT treatment showed a significant restoration of mitophagy, decreased DNA damage foci formation, and delayed cellular senescence in SAECs.”

In the paper

“Parkin overexpression along with MitoT treatment showed a significant restoration of mitophagy, decreased DNA damage foci formation, and delayed cellular senescence in SAECs.”

In the paper

“Parkin overexpression along with MitoT treatment showed a significant restoration of mitophagy, decreased DNA damage foci formation, and delayed cellular senescence in SAECs.”

In the paper

“Cigarette smoke (CS)-induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema, a disease characterized by premature lung aging (1–3).”

What the sources say

• Not checked yetcites [1] Nyunoya T., Monick M. M., Klingelhutz A., Yarovinsky T. O., Cagley J. R., Hunninghake G. W. (2006) Cigarette smoke induces cellular senescence. Am. J. Respir. Cell Mol. Biol. 35, 681–688 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [2] Nyunoya T., Monick M. M., Klingelhutz A. L., Glaser H., Cagley J. R., Brown C. O., Matsumoto E., Aykin-Burns N., Spitz D. R., Oshima J., Hunninghake G. W. (2009) Cigarette smoke induces cellular senescence via Werner’s syndrome protein down-regulation. Am. J. Respir. Crit. Care Med. 179, 279–287 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [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

In the paper

“there is accumulating evidence suggesting a critical role of mitochondrial dysfunction in airway diseases (9–12).”

What the sources say

• Not checked yetcites [9] Tait S. W., Green D. R. (2012) Mitochondria and cell signalling. J. Cell Sci. 125, 807–815 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [10] Jia L., Liu Z., Sun L., Miller S. S., Ames B. N., Cotman C. W., Liu J. (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid. Invest. Ophthalmol. Vis. Sci. 48, 339–348 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [11] Guo L., Li L., Wang W., Pan Z., Zhou Q., Wu Z. (2012) Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells. Biochim. Biophys. Acta 1822, 852–861 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [12] Zuckerbraun B. S., Chin B. Y., Bilban M., d’Avila J. C., Rao J., Billiar T. R., Otterbein L. E. (2007) Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106 [DOI] [PubMed] [Google Scholar] source

In the paper

“Lung airway structural cells (epithelium and fibroblasts) show increased cellular senescence (irreversible growth arrest) induced by CS in vitro and in vivo (4–6).”

What the sources say

• Not checked yetcites [4] Hara H., Araya J., Takasaka N., Fujii S., Kojima J., Yumino Y., Shimizu K., Ishikawa T., Numata T., Kawaishi M., Saito K., Hirano J., Odaka M., Morikawa T., Hano H., Nakayama K., Kuwano K. (2012) Involvement of creatine kinase B in cigarette smoke-induced bronchial epithelial cell senescence. Am. J. Respir. Cell Mol. Biol. 46, 306–312 [DOI] [PubMed] [Google Scholar] source
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• Not checked yetcites [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

In the paper

“These data suggest that increased cytosolic p53 has a role in inhibiting Parkin mitochondrial translocation.”

In the paper

“These results confirm the notion that mitochondrial dysfunction and impaired mitophagy are some of the important prerequisite factors to cause cellular senescence.”

In the paper

“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.”

In the paper

“Altogether, CSE stress-induced perinuclear mitochondrial accumulation was associated with nuclear ROS and DNA damage.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

“We further show that CSE-induced perinuclear mitochondrial accumulation results in DNA damage and hence cellular senescence.”

In the paper

“SAECs from patients with COPD also displayed reduced Parkin mitochondrial translocation in the presence of CCCP compared to cells from normal subjects, implicating impaired mitophagy (Fig. 7E, F).”

In the paper

“These results show that mitophagy plays a critical role during the process of cellular senescence, whereas decreased mitophagy augments CSE stress-induced senescence, and Parkin overexpression along with mitochondria-targeted antioxidants delays cellular senescence in human SAECs.”

In the paper

“Senescence of these cells plays direct (impaired re-epithelialization) and indirect (increased release of inflammatory mediators) contributing roles in the pathogenesis of COPD/emphysema (1–3, 46).”

What the sources say

• Not checked yetcites [1] Nyunoya T., Monick M. M., Klingelhutz A., Yarovinsky T. O., Cagley J. R., Hunninghake G. W. (2006) Cigarette smoke induces cellular senescence. Am. J. Respir. Cell Mol. Biol. 35, 681–688 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [2] Nyunoya T., Monick M. M., Klingelhutz A. L., Glaser H., Cagley J. R., Brown C. O., Matsumoto E., Aykin-Burns N., Spitz D. R., Oshima J., Hunninghake G. W. (2009) Cigarette smoke induces cellular senescence via Werner’s syndrome protein down-regulation. Am. J. Respir. Crit. Care Med. 179, 279–287 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [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 yetcites [46] Dagouassat M., Gagliolo J. M., Chrusciel S., Bourin M. C., Duprez C., Caramelle P., Boyer L., Hue S., Stern J. B., Validire P., Longrois D., Norel X., Dubois-Randé J. L., Le Gouvello S., Adnot S., Boczkowski J. (2013) The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts. Am. J. Respir. Crit. Care Med. 187, 703–714 [DOI] [PubMed] [Google Scholar] source

In the paper

“CS is shown to induce cellular senescence in lung structural cells, including SAECs, bronchial epithelial cells, and fibroblasts (1, 2, 5, 6).”

What the sources say

• Not checked yetcites [1] Nyunoya T., Monick M. M., Klingelhutz A., Yarovinsky T. O., Cagley J. R., Hunninghake G. W. (2006) Cigarette smoke induces cellular senescence. Am. J. Respir. Cell Mol. Biol. 35, 681–688 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [2] Nyunoya T., Monick M. M., Klingelhutz A. L., Glaser H., Cagley J. R., Brown C. O., Matsumoto E., Aykin-Burns N., Spitz D. R., Oshima J., Hunninghake G. W. (2009) Cigarette smoke induces cellular senescence via Werner’s syndrome protein down-regulation. Am. J. Respir. Crit. Care Med. 179, 279–287 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [5] Nyunoya T., Mebratu Y., Contreras A., Delgado M., Chand H. S., Tesfaigzi Y. (2014) Molecular processes that drive cigarette smoke-induced epithelial cell fate of the lung. Am. J. Respir. Cell Mol. Biol. 50, 471–482 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [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

In the paper

“These results show that mitophagy plays a critical role during the process of cellular senescence, whereas decreased mitophagy augments CSE stress-induced senescence, and Parkin overexpression along with mitochondria-targeted antioxidants delays cellular senescence in human SAECs.”

In the paper

“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.”

In the paper

“In cells, most of the ROS is produced by mitochondria, and CS is known to cause mitochondrial dysfunction (9–12, 47).”

What the sources say

• Not checked yetcites [9] Tait S. W., Green D. R. (2012) Mitochondria and cell signalling. J. Cell Sci. 125, 807–815 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [10] Jia L., Liu Z., Sun L., Miller S. S., Ames B. N., Cotman C. W., Liu J. (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid. Invest. Ophthalmol. Vis. Sci. 48, 339–348 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [11] Guo L., Li L., Wang W., Pan Z., Zhou Q., Wu Z. (2012) Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells. Biochim. Biophys. Acta 1822, 852–861 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [12] Zuckerbraun B. S., Chin B. Y., Bilban M., d’Avila J. C., Rao J., Billiar T. R., Otterbein L. E. (2007) Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [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

In the paper

“Perinuclear mitochondrial clustering associated with increased mtROS led to an increase in nuclear ROS, which may be due to the dysfunctional mitochondria itself.”

In the paper

“In cells, most of the ROS is produced by mitochondria, and CS is known to cause mitochondrial dysfunction (9–12, 47).”

What the sources say

• Not checked yetcites [9] Tait S. W., Green D. R. (2012) Mitochondria and cell signalling. J. Cell Sci. 125, 807–815 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [10] Jia L., Liu Z., Sun L., Miller S. S., Ames B. N., Cotman C. W., Liu J. (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid. Invest. Ophthalmol. Vis. Sci. 48, 339–348 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [11] Guo L., Li L., Wang W., Pan Z., Zhou Q., Wu Z. (2012) Mitochondrial reactive oxygen species mediates nicotine-induced hypoxia-inducible factor-1α expression in human non-small cell lung cancer cells. Biochim. Biophys. Acta 1822, 852–861 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [12] Zuckerbraun B. S., Chin B. Y., Bilban M., d’Avila J. C., Rao J., Billiar T. R., Otterbein L. E. (2007) Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [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

In the paper

“These results show that mitophagy plays a critical role during the process of cellular senescence, whereas decreased mitophagy augments CSE stress-induced senescence, and Parkin overexpression along with mitochondria-targeted antioxidants delays cellular senescence in human SAECs.”

In the paper

“Recent findings along with our data suggest an important role of cellular senescence in both lung fibroblasts and epithelial cells (particularly SAECs) in the pathogenesis of COPD/emphysema (1, 6).”

What the sources say

• Not checked yetcites [1] Nyunoya T., Monick M. M., Klingelhutz A., Yarovinsky T. O., Cagley J. R., Hunninghake G. W. (2006) Cigarette smoke induces cellular senescence. Am. J. Respir. Cell Mol. Biol. 35, 681–688 [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [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

In the paper

“Persistent increase in ROS levels is a well-known factor mediating DNA damage and cellular senescence (42, 48), where mitochondria may play a critical role.”

What the sources say

• Not checked yetcites [42] Muñoz-Espín D., Serrano M. (2014) Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 [DOI] [PubMed] [Google Scholar] source
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In the paper

“Nevertheless, these findings provide convincing evidence that perinuclear mitochondrial clustering is a critical step to induce DNA damage during the pathogenesis of COPD/emphysema after chronic CS exposures.”

In the paper

“These results are in agreement with the previous reports showing impaired mitophagy occurring during mitochondrial elongation (49).”

What the sources say

• Not checked yetcites [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

In the paper

“As expected, increased expression of senescence markers (p16 and p21) was observed in both lung epithelia (alveolar and bronchial) and fibroblasts of mice with emphysema (6).”

What the sources say

• Not checked yetcites [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

In the paper

“In our study, although the total Parkin levels were not significantly altered between control and CSE-treated cells, CCCP-mediated Parkin translocation to mitochondria was reduced by CSE, suggesting impaired clearance of damaged mitochondria.”

In the paper

“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).”

What the sources say

• Not checked yetcites [42] Muñoz-Espín D., Serrano M. (2014) Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 [DOI] [PubMed] [Google Scholar] source
• Not checked yetcites [45] Vigneron A., Vousden K. H. (2010) p53, ROS and senescence in the control of aging. Aging (Albany, N.Y. Online) 2, 471–474 [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“mtROS has been shown as a key inducer for premature aging, and mtROS inhibitor reduces senescence in bone marrow mesenchymal stem cells (52, 53).”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“CS stress induces mitochondrial structural and functional changes by interfering with mitochondrial quality control machinery.”

In the paper

“A combination of Parkin overexpression and MitoT shows promising results in restoring the defective mitophagy and hence delaying cellular senescence.”