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Article ; Online: Disruption of the Molecular Regulation of Mitochondrial Metabolism in Airway and Lung Epithelial Cells by Cigarette Smoke: Are Aldehydes the Culprit?

Tulen, Christy B M / Opperhuizen, Antoon / van Schooten, Frederik-Jan / Remels, Alexander H V

2023 Volume 12, Issue 2

Abstract: Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of ... ...

Abstract	Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. Mitochondrial dysfunction is suggested to be mechanistically and causally involved in the pathogenesis of smoking-associated lung diseases such as COPD. Cigarette smoke (CS) has been shown to impair the molecular regulation of mitochondrial metabolism and content in epithelial cells of the airways and lungs. Although it is unknown which specific chemicals present in CS are responsible for this, it has been suggested that aldehydes may be involved. Therefore, it has been proposed by the World Health Organization to regulate aldehydes in commercially-available cigarettes. In this review, we comprehensively describe and discuss the impact of acetaldehyde, acrolein, and formaldehyde on mitochondrial function and content and the molecular pathways controlling this (biogenesis versus mitophagy) in epithelial cells of the airways and lungs. In addition, potential therapeutic applications targeting (aldehyde-induced) mitochondrial dysfunction, as well as regulatory implications, and the necessary required future studies to provide scientific support for this regulation, have been covered in this review.
MeSH term(s)	Nicotiana/adverse effects ; Aldehydes/metabolism ; Acrolein/toxicity ; Acrolein/metabolism ; Cigarette Smoking/adverse effects ; Lung/pathology ; Pulmonary Disease, Chronic Obstructive/pathology ; Epithelial Cells/metabolism ; Formaldehyde ; Acetaldehyde/toxicity ; Acetaldehyde/metabolism ; Mitochondria/metabolism
Chemical Substances	Aldehydes ; Acrolein (7864XYD3JJ) ; Formaldehyde (1HG84L3525) ; Acetaldehyde (GO1N1ZPR3B)
Language	English
Publishing date	2023-01-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12020299
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Article ; Online: Impact of sub-acute acrolein inhalation on the molecular regulation of mitochondrial metabolism in rat lung.

Tulen, C B M / Leermakers, P A / Schrieder, S E / van Schooten, F J / Opperhuizen, A / Remels, A H V

Toxicology letters

2023 Volume 378, Page(s) 19–30

Abstract: ... acrolein by whole-body inhalation (5 h/day, 5 days/week for 4 weeks). Acrolein exposure induced a general ...

Abstract	Nowadays, mitochondria are recognized as key players in the pathogenesis of a variety of smoking-associated lung diseases. Acrolein, a component of cigarette smoke, is a known driver of biological mechanisms underlying smoking-induced respiratory toxicity. The impact of sub-acute acrolein inhalation in vivo on key processes controlling mitochondrial homeostasis in cells of the airways however is unknown. In this study, we investigated the activity/abundance of a myriad of molecules critically involved in mitochondrial metabolic pathways and mitochondrial quality control processes (mitochondrial biogenesis and mitophagy) in the lungs of Sprague-Dawley rats that were sub-acutely exposed to filtered air or 3 ppm acrolein by whole-body inhalation (5 h/day, 5 days/week for 4 weeks). Acrolein exposure induced a general inflammatory response in the lung as gene expression analysis revealed an increased expression of Icam1 and Cinc1 (p < 0.1; p < 0.05). Acrolein significantly decreased enzyme activity of hydroxyacyl-Coenzyme A dehydrogenase (p < 0.01), and decreased Pdk4 transcript levels (p < 0.05), suggestive of acrolein-induced changes in metabolic processes. Investigation of constituents of the mitochondrial biogenesis pathways and mitophagy machinery revealed no pronounced alterations. In conclusion, sub-acute inhalation of acrolein did not affect the regulation of mitochondrial metabolism and quality control, which is in contrast to more profound changes after acute exposure in other studies.
MeSH term(s)	Rats ; Animals ; Acrolein/toxicity ; Rats, Sprague-Dawley ; Lung ; Mitochondria ; Lung Diseases/pathology
Chemical Substances	Acrolein (7864XYD3JJ)
Language	English
Publishing date	2023-02-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2023.02.003
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Article ; Online: Impact of More Intense Smoking Parameters and Flavor Variety on Toxicant Levels in Emissions of a Heated Tobacco Product.

Davigo, Michele / Klerx, Walther N M / van Schooten, Frederik-Jan / Opperhuizen, Antoon / Remels, Alexander H V / Talhout, Reinskje

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco

2023 Volume 26, Issue 5, Page(s) 571–579

Abstract: Introduction: IQOS HEETS are promoted as reduced-risk alternatives to cigarettes. Although some studies have investigated the chemical composition of HEETS emissions, little is known on whether toxicant levels in such emissions are affected by different ...

Abstract	Introduction: IQOS HEETS are promoted as reduced-risk alternatives to cigarettes. Although some studies have investigated the chemical composition of HEETS emissions, little is known on whether toxicant levels in such emissions are affected by different puffing parameters and flavor varieties. This has important implications when assessing actual human exposure, since IQOS users develop a specific and personalized puffing behavior and may use different HEETS variants. Methods: This study measured the levels of nicotine, total particulate matter, carbonyl compounds, and tobacco-specific nitrosamines (TSNAs) in the emissions of nine differently flavored HEETS and two cigarettes (1R6F and Marlboro Red, MR). Emissions from Yellow HEETS, 1R6F, and MR were collected using the World Health Organization Intense smoking regime and four more intense smoking regimes. Results: Yellow HEETS aerosol contained lower levels of toxicants compared to 1R6F and MR smoke. More intense smoking regimes increased carbonyl release in cigarette smoke, whereas only higher puff frequency led to lower levels of toxicants in Yellow HEETS aerosol. Some HEETS varieties exhibited higher levels of formaldehyde and TSNAs in their aerosols compared to Yellow HEETS. Conclusions: Puff frequency was identified as the only smoking parameter that significantly lowered the release of almost all toxicants in Yellow HEETS, whereas a combination of higher puff volume and puff duration led to increased levels of some carbonyls. Differences in toxicant levels between various commercially available HEETS have important implications when assessing their health impact, as their consumption might induce different toxicant exposure and health effects. Implications: HEETS release about half as much nicotine and substantially lower levels of toxicants compared to cigarettes. Literature data showed that puffing intensity is increased in cigarette smokers switching to HEETS, maybe in reaction to these lower nicotine levels. Our results show a differential impact of increased puff frequency, puff duration, and puff volume in the release of toxicants from HEETS. Thus, industry-independent studies on puff topography are critical to make choices for the most relevant puffing regime for heated tobacco product regulation. Regulators should consider evaluating the health impact of multiple HEETS varieties, as the tobacco filler composition significantly affects the release of certain toxicants.
MeSH term(s)	Tobacco Products/analysis ; Flavoring Agents/analysis ; Humans ; Nicotine/analysis ; Particulate Matter/analysis ; Nitrosamines/analysis ; Nicotiana/chemistry ; Aerosols/analysis ; Smoke/analysis ; Smoking
Chemical Substances	Flavoring Agents ; Nicotine (6M3C89ZY6R) ; Particulate Matter ; Nitrosamines ; Aerosols ; Smoke
Language	English
Publishing date	2023-11-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1452315-2
ISSN	1469-994X ; 1462-2203
ISSN (online)	1469-994X
ISSN	1462-2203
DOI	10.1093/ntr/ntad238
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Zs.A 5789: Show issues

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Article ; Online: Alterations in the molecular control of mitochondrial turnover in COPD lung and airway epithelial cells.

Tulen, Christy B M / van de Wetering, Cheryl / Schiffers, Caspar H J / Weltjens, Ellen / Benedikter, Birke J / Leermakers, Pieter A / Boukhaled, Juliana H / Drittij, Marie-José / Schmeck, Bernd T / Reynaert, Niki L / Opperhuizen, Antoon / van Schooten, Frederik-Jan / Remels, Alexander H V

Scientific reports

2024 Volume 14, Issue 1, Page(s) 4821

Abstract: Abnormal mitochondria have been observed in bronchial- and alveolar epithelial cells of patients with chronic obstructive pulmonary disease (COPD). However, it is unknown if alterations in the molecular pathways regulating mitochondrial turnover ( ... ...

Abstract	Abnormal mitochondria have been observed in bronchial- and alveolar epithelial cells of patients with chronic obstructive pulmonary disease (COPD). However, it is unknown if alterations in the molecular pathways regulating mitochondrial turnover (mitochondrial biogenesis vs mitophagy) are involved. Therefore, in this study, the abundance of key molecules controlling mitochondrial turnover were assessed in peripheral lung tissue from non-COPD patients (n = 6) and COPD patients (n = 11; GOLDII n = 4/11; GOLDIV n = 7/11) and in both undifferentiated and differentiated human primary bronchial epithelial cells (PBEC) from non-COPD patients and COPD patients (n = 4-7 patients/group). We observed significantly decreased transcript levels of key molecules controlling mitochondrial biogenesis (PPARGC1B, PPRC1, PPARD) in peripheral lung tissue from severe COPD patients. Interestingly, mRNA levels of the transcription factor TFAM (mitochondrial biogenesis) and BNIP3L (mitophagy) were increased in these patients. In general, these alterations were not recapitulated in undifferentiated and differentiated PBECs with the exception of decreased PPARGC1B expression in both PBEC models. Although these findings provide valuable insight in these pathways in bronchial epithelial cells and peripheral lung tissue of COPD patients, whether or not these alterations contribute to COPD pathogenesis, underlie changes in mitochondrial function or may represent compensatory mechanisms remains to be established.
MeSH term(s)	Humans ; Lung/pathology ; Pulmonary Disease, Chronic Obstructive/pathology ; Mitochondrial Turnover ; Mitochondria/metabolism ; Epithelial Cells/metabolism ; RNA-Binding Proteins/metabolism
Chemical Substances	PPARGC1B protein, human ; RNA-Binding Proteins
Language	English
Publishing date	2024-02-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-55335-8
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Article ; Online: Acrolein inhalation acutely affects the regulation of mitochondrial metabolism in rat lung.

Tulen, C B M / Snow, S J / Leermakers, P A / Kodavanti, U P / van Schooten, F J / Opperhuizen, A / Remels, A H V

Toxicology

2022 Volume 469, Page(s) 153129

Abstract: ... by inhalation (nose-only; 0-4 ppm), 4 h/day for 1 or 2 consecutive days (n = 6/group). Subsequently ...

Abstract	Exposure of the airways to cigarette smoke (CS) is the primary risk factor for developing several lung diseases such as Chronic Obstructive Pulmonary Disease (COPD). CS consists of a complex mixture of over 6000 chemicals including the highly reactive α,β-unsaturated aldehyde acrolein. Acrolein is thought to be responsible for a large proportion of the non-cancer disease risk associated with smoking. Emerging evidence suggest a key role for CS-induced abnormalities in mitochondrial morphology and function in airway epithelial cells in COPD pathogenesis. Although in vitro studies suggest acrolein-induced mitochondrial dysfunction in airway epithelial cells, it is unknown if in vivo inhalation of acrolein affects mitochondrial content or the pathways controlling this. In this study, rats were acutely exposed to acrolein by inhalation (nose-only; 0-4 ppm), 4 h/day for 1 or 2 consecutive days (n = 6/group). Subsequently, the activity and abundance of key constituents of mitochondrial metabolic pathways as well as expression of critical proteins and genes controlling mitochondrial biogenesis and mitophagy were investigated in lung homogenates. A transient decreasing response in protein and transcript abundance of subunits of the electron transport chain complexes was observed following acrolein inhalation. Moreover, acrolein inhalation caused a decreased abundance of key regulators associated with mitochondrial biogenesis, respectively a differential response on day 1 versus day 2. Abundance of components of the mitophagy machinery was in general unaltered in response to acrolein exposure in rat lung. Collectively, this study demonstrates that acrolein inhalation acutely and dose-dependently disrupts the molecular regulation of mitochondrial metabolism in rat lung. Hence, understanding the effect of acrolein on mitochondrial function will provide a scientifically supported reasoning to shortlist aldehydes regulation in tobacco smoke.
MeSH term(s)	Acrolein/metabolism ; Administration, Inhalation ; Aldehydes/metabolism ; Animals ; Lung ; Mitochondria ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; Rats ; Nicotiana/chemistry
Chemical Substances	Aldehydes ; Acrolein (7864XYD3JJ)
Language	English
Publishing date	2022-02-10
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2022.153129
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Article ; Online: Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci.

Aghapour, Mahyar / Tulen, Christy B M / Abdi Sarabi, Mohsen / Weinert, Sönke / Müsken, Mathias / Relja, Borna / van Schooten, Frederik-Jan / Jeron, Andreas / Braun-Dullaeus, Rüdiger / Remels, Alexander H / Bruder, Dunja

Cells

2022 Volume 11, Issue 11

Abstract: Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, ...

Abstract	Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with
MeSH term(s)	Bronchi/metabolism ; Cigarette Smoking ; Epithelial Cells/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Streptococcus pneumoniae/metabolism ; Nicotiana/adverse effects ; Nicotiana/metabolism
Chemical Substances	Mitochondrial Proteins
Language	English
Publishing date	2022-05-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11111771
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Article ; Online: Dysregulated mitochondrial metabolism upon cigarette smoke exposure in various human bronchial epithelial cell models.

Tulen, Christy B M / Wang, Ying / Beentjes, Daan / Jessen, Phyllis J J / Ninaber, Dennis K / Reynaert, Niki L / van Schooten, Frederik-Jan / Opperhuizen, Antoon / Hiemstra, Pieter S / Remels, Alexander H V

Disease models & mechanisms

2022 Volume 15, Issue 3

Abstract: Exposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely ... ...

Abstract	Exposure to cigarette smoke (CS) is the primary risk factor for developing chronic obstructive pulmonary disease. The impact of CS exposure on the molecular mechanisms involved in mitochondrial quality control in airway epithelial cells is incompletely understood. Undifferentiated or differentiated primary bronchial epithelial cells were acutely/chronically exposed to whole CS (WCS) or CS extract (CSE) in submerged or air-liquid interface conditions. Abundance of key regulators controlling mitochondrial biogenesis, mitophagy and mitochondrial dynamics was assessed. Acute exposure to WCS or CSE increased the abundance of components of autophagy and receptor-mediated mitophagy in all models. Although mitochondrial content and dynamics appeared to be unaltered in response to CS, changes in both the molecular control of mitochondrial biogenesis and a shift toward an increased glycolytic metabolism were observed in particular in differentiated cultures. These alterations persisted, at least in part, after chronic exposure to WCS during differentiation and upon subsequent discontinuation of WCS exposure. In conclusion, smoke exposure alters the regulation of mitochondrial metabolism in airway epithelial cells, but observed alterations may differ between various culture models used. This article has an associated First Person interview with the joint first authors of the paper.
MeSH term(s)	Bronchi ; Cigarette Smoking ; Epithelial Cells ; Humans ; Mitochondria ; Mitophagy ; Pulmonary Disease, Chronic Obstructive/etiology ; Nicotiana/adverse effects
Language	English
Publishing date	2022-03-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049247
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Article ; Online: Iron deficiency-induced loss of skeletal muscle mitochondrial proteins and respiratory capacity; the role of mitophagy and secretion of mitochondria-containing vesicles.

Leermakers, Pieter A / Remels, Alexander H V / Zonneveld, Marijke I / Rouschop, Kasper M A / Schols, Annemie M W J / Gosker, Harry R

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2020 Volume 34, Issue 5, Page(s) 6703–6717

Abstract: Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency-induced ... ...

Abstract	Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency-induced loss of skeletal muscle mitochondria is caused by increased mitochondrial clearance. To study this, C2C12 myotubes were subjected to the iron chelator deferiprone. Mitochondrial parameters and key constituents of mitophagy pathways were studied in presence or absence of pharmacological autophagy inhibition or knockdown of mitophagy-related proteins. Furthermore, it was explored if mitochondria were present in extracellular vesicles (EV). Iron chelation resulted in an increase in BCL2/Adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like gene and protein levels, and the appearance of mitochondria encapsulated by lysosome-like vesicular structures in myotubes. Moreover, mitochondria were secreted via EV. These changes were associated with cellular mitochondrial impairments. These impairments were unaltered by autophagy inhibition, knockdown of mitophagy-related proteins BNIP3 and BNIP3L, or knockdown of their upstream regulator hypoxia-inducible factor 1 alpha. In conclusion, mitophagy is not essential for development of iron deficiency-induced reductions in mitochondrial proteins or respiratory capacity. The secretion of mitochondria-containing EV could present an additional pathway via which mitochondria can be cleared from iron chelation-exposed myotubes.
MeSH term(s)	Animals ; Iron/deficiency ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondria, Muscle/metabolism ; Mitochondria, Muscle/pathology ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitophagy ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Reactive Oxygen Species ; Secretory Vesicles/metabolism
Chemical Substances	BNip3 protein, mouse ; Membrane Proteins ; Mitochondrial Proteins ; Nix protein, mouse ; Reactive Oxygen Species ; Iron (E1UOL152H7)
Language	English
Publishing date	2020-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201901815R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle.

Leermakers, Pieter A / Remels, Alexander H V / Langen, Ramon C J / Schols, Annemie M W J / Gosker, Harry R

BMC pulmonary medicine

2020 Volume 20, Issue 1, Page(s) 20

Abstract: Background: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore ...

Abstract	Background: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. Methods: We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. Results: Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. Conclusions: These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.
MeSH term(s)	Acute Lung Injury/chemically induced ; Acute Lung Injury/metabolism ; Acute Lung Injury/physiopathology ; Animals ; Inflammation/metabolism ; Inflammation/physiopathology ; Lipopolysaccharides/adverse effects ; Mice ; Mitochondria, Muscle/metabolism ; Mitochondrial Dynamics/genetics ; Mitophagy/physiology ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/physiopathology ; Organelle Biogenesis ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Signal Transduction
Chemical Substances	Lipopolysaccharides
Language	English
Publishing date	2020-01-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2059871-3
ISSN	1471-2466 ; 1471-2466
ISSN (online)	1471-2466
ISSN	1471-2466
DOI	10.1186/s12890-020-1047-8
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Article ; Online: Hypoxia-induced mitochondrial abnormalities in cells of the placenta.

Vangrieken, Philippe / Al-Nasiry, Salwan / Bast, Aalt / Leermakers, Pieter A / Tulen, Christy B M / Janssen, Ger M J / Kaminski, Iris / Geomini, Iris / Lemmens, Titus / Schiffers, Paul M H / van Schooten, Frederik J / Remels, Alex H V

PloS one

2021 Volume 16, Issue 1, Page(s) e0245155

Abstract: Introduction: Impaired utero-placental perfusion is a well-known feature of early preeclampsia and is associated with placental hypoxia and oxidative stress. Although aberrations at the level of the mitochondrion have been implicated in PE ... ...

Abstract	Introduction: Impaired utero-placental perfusion is a well-known feature of early preeclampsia and is associated with placental hypoxia and oxidative stress. Although aberrations at the level of the mitochondrion have been implicated in PE pathophysiology, whether or not hypoxia-induced mitochondrial abnormalities contribute to placental oxidative stress is unknown. Methods: We explored whether abnormalities in mitochondrial metabolism contribute to hypoxia-induced placental oxidative stress by using both healthy term placentae as well as a trophoblast cell line (BeWo cells) exposed to hypoxia. Furthermore, we explored the therapeutic potential of the antioxidants MitoQ and quercetin in preventing hypoxia-induced placental oxidative stress. Results: Both in placental explants as well as BeWo cells, hypoxia resulted in reductions in mitochondrial content, decreased abundance of key molecules involved in the electron transport chain and increased expression and activity of glycolytic enzymes. Furthermore, expression levels of key regulators of mitochondrial biogenesis were decreased while the abundance of constituents of the mitophagy, autophagy and mitochondrial fission machinery was increased in response to hypoxia. In addition, placental hypoxia was associated with increased oxidative stress, inflammation, and apoptosis. Moreover, experiments with MitoQ revealed that hypoxia-induced reactive oxygen species originated from the mitochondria in the trophoblasts. Discussion: This study is the first to demonstrate that placental hypoxia is associated with mitochondrial-generated reactive oxygen species and significant alterations in the molecular pathways controlling mitochondrial content and function. Furthermore, our data indicate that targeting mitochondrial oxidative stress may have therapeutic benefit in the management of pathologies related to placental hypoxia.
MeSH term(s)	Cell Hypoxia ; Cell Line ; Female ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Organelle Biogenesis ; Oxidative Stress ; Pre-Eclampsia/metabolism ; Pre-Eclampsia/pathology ; Pregnancy ; Reactive Oxygen Species/metabolism ; Trophoblasts/metabolism ; Trophoblasts/pathology
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2021-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0245155
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