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

Ahmad, Tanveer; Sundar, Isaac K.; Lerner, Chad; Gerloff, Janice; Tormos, Ana M.; Yao, Hongwei; Rahman, Irfan

doi:10.1096/fj.14-268276

Cited by 222 publications

(265 citation statements)

References 60 publications

Supporting

Mentioning

243

Contrasting

Unclassified

Order By: Relevance

“…A COPD specific impaired mitophagy could be one of these mechanisms. Indeed, a decreased Parkin expression was reported in lung tissues of COPD patients (Ahmad et al, 2015; Ito et al, 2015). Interestingly, this reduction was correlated with a decrease in lung function in COPD patients (Ito et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

“…However, we think this possibility unlikely because: (a) Smoker controls and COPD patients suffered from similar cancer histological types, (b) biopsies were harvested at a distance from the tumor and were verified to be free of malignant cells, and (c) primary cultures of lung fibroblasts did not exhibit Cancer Associated Fibroblasts markers (data not shown). Cigarette smoke can trigger mitochondrial dysfunction in COPD fibroblasts since lung epithelial cells and fibroblasts exposed to cigarette smoke exhibit an increase in mitochondrial ROS, reduced ATP levels, and changes in mitochondria structure (Ahmad et al, 2015), (Hoffmann et al, 2013). However, other factors probably contribute to mitochondrial dysfunction in COPD cells since in the present study, the smoking history of COPD and control smokers was similar.…”

Section: Discussionmentioning

confidence: 99%

“…Studies performed in cells exposed to cigarette smoke support a cause–effect relationship between impaired mitophagy, mitochondrial dysfunction, and increased accelerated senescence in COPD. In fact, Ahmad and coworkers (Ahmad et al, 2015) showed that overexpression of Parkin reduces cigarette smoke‐induced DNA damage and cellular senescence when used in combination with a scavenger of mitochondria ROS. In addition, Ito and coworkers demonstrated that the knockdown of Pink1 or Parkin in human bronchial epithelial cells (HBECs) enhanced cellular senescence induced by cigarette smoke exposure (Ito et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, we observed a decreased expression of NRF‐1 in fibroblasts from COPD patients treated with hemin, suggesting that another mechanism could be involved. Indeed, cytoplasmic p53, which accumulates in senescence, interacts with Parkin and prevents its translocation to dysfunctional mitochondria, thus suppressing mitophagy (Ahmad et al, 2015; Hoshino et al, 2013). Similarly, expression of PINK‐1 is low in aging lungs, which participate in the deletion of mitophagy (Bueno et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, defective mitophagy has been already involved in lung cellular senescence upon exposure to CS in vitro and in vivo (Ahmad et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

et al. 2018

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)‐1 plays a critical role in defending the lung against oxidative stress and inflammation. Therefore, we investigated whether pharmacological induction of HO‐1 by chronic hemin treatment attenuates senescence and improves dysfunctional mitochondria in COPD fibroblasts. Fibroblasts from smoker controls (S‐C) and COPD patients were isolated from lung biopsies. Fibroblasts were long‐term cultured in the presence or absence of hemin, and/or ZnPP or QC‐15 (HO‐1 inhibitors). Lung fibroblasts from smokers and COPD patients displayed in long‐term culture a senescent phenotype, characterized by a reduced replicative capacity, an increased senescence and inflammatory profile. These parameters were significantly higher in senescent COPD fibroblasts which also exhibited decreased mitochondrial activity (respiration, glycolysis, and ATP levels) which led to an increased production of ROS, and mitochondria biogenesis and impaired mitophagy process. Exposure to hemin increased the gene and protein expression level of HO‐1 in fibroblasts and diminished ROS levels, senescence, the inflammatory profile and simultaneously rescued mitochondria dysfunction by restoring mitophagy in COPD cells. The effects of hemin were abolished by a cotreatment with ZnPP or QC‐15. We conclude that HO‐1 attenuates senescence in COPD fibroblasts by protecting, at least in part, against mitochondria dysfunction and restoring mitophagy.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Indeed, defective mitophagy has been already involved in lung cellular senescence upon exposure to CS in vitro and in vivo (Ahmad et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

et al. 2018

View full text Add to dashboard Cite

show abstract

Mitochondrial dysfunction and cell senescence: deciphering a complex relationship

2019

View full text Add to dashboard Cite

Cellular senescence and mitochondrial dysfunction have both been defined as classical hallmarks of the ageing process. Here, we review the intricate relationship between the two. In the context of ageing, it is now well regarded that cellular senescence is a key driver in both ageing and the onset of a number of age‐related pathologies. Emerging evidence has pinpointed mitochondria as one of the key modulators in the development of the senescence phenotype, particularly the pro‐inflammatory senescence associated secretory phenotype (SASP). This review focuses on the contribution of homeostatic mechanisms, as well as of reactive oxygen species and mitochondrial metabolites in the senescence programme. Furthermore, we discuss emerging pathways and mitochondrial‐mediated mechanisms that may be influencing the SASP and, subsequently, explore how these may be exploited to open up new therapeutic avenues.

show abstract

Touchable Electrochemical Hydrogel Sensor for Detection of Reactive Oxygen Species‐induced Cellular Senescence in Articular Chondrocytes

Kim

Song

Ryplida

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

In this study, a reactive oxygen species (ROS)-responsive hydrogel sensor (PD/ MnO 2 hydrogel) is developed that can efficiently detect senescent cells. Using immature murine articular chondrocytes with serial passages, the sensor can identify small interfering RNA (siRNA) knockdown of peroxisome proliferatoractivated receptor-alpha (PPARα) based on the concentration of ROS in cells, simultaneously maintaining its balance via scavenging activity to prevent cartilage degradation in osteoarthritis (OA). The hydrogel sensor exhibits a change in electronic properties, with a distinct resistance from 201.9 kΩ for P0 to 362.9 kΩ for P3, and fluorescence off/on performance with an increase in passaging time. In vitro investigation using PPARα-specific siRNA reveals a correlation between pressure sensitivity and senescent activity, wherein an elevation in observed signal occurred (41.5%). In vivo analysis reveals significant decrease in degradation of the cartilage of both young, 3 months old aged, 18 months old, and PPARα −/− mice compared to PPARα +/+ mice based on safranin O stains. The expression level of interleukin-1β is reduced in the cartilage of aged PPARα −/− mice after implantation with hydrogel, indicating the potential of PD/MnO 2 hydrogel as a therapeutic modality against OA.

show abstract

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

Cited by 222 publications

References 60 publications

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Mitochondrial dysfunction and cell senescence: deciphering a complex relationship

Touchable Electrochemical Hydrogel Sensor for Detection of Reactive Oxygen Species‐induced Cellular Senescence in Articular Chondrocytes

Contact Info

Product

Resources

About