Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander?

Rowlands, David J.

doi:10.1016/j.pharmthera.2016.06.019

Cited by 35 publications

(32 citation statements)

References 138 publications

(137 reference statements)

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“…Mitochondrial dysfunction is a feature of both senescence and ageing . Mitochondrial DNA, membranous lipids and proteins are highly susceptible to oxidative damage, causing respiratory uncoupling and increased formation of superoxide . The latter in turn contributes to further mitochondrial damage, as part of a cycle that ultimately leads to dysmorphic and impaired mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulated Nox4 may contribute to IPF‐LF mitochondrial dysfunction, particularly as Nox4 can localize in mitochondria, and its expression is stimulated by mitochondrial‐derived ROS . Another important pathological feature of mitochondrial dysfunction is the cellular release of fragmented, oxidised mtDNA, which acts as danger associated molecular pattern (DAMP) . IPF‐LFs in culture, when compared to Ctrl‐LF, release increased amounts of mtDNA .…”

Section: Discussionmentioning

confidence: 99%

“…19 Mitochondrial DNA, membranous lipids and proteins are highly susceptible to oxidative damage, causing respiratory uncoupling and increased formation of superoxide. 33 The latter in turn contributes to further mitochondrial damage, as part of a cycle that ultimately leads to dysmorphic and impaired mitochondria. In this study, IPF-LF mitochondrial dysfunction was shown by increases in MitoSOX and NAO fluorescence, which were not evident in Ctrl-LFs.…”

Section: Discussionmentioning

confidence: 99%

“…31 Another important pathological feature of mitochondrial dysfunction is the cellular release of fragmented, oxidised mtDNA, which acts as danger associated molecular pattern (DAMP). 33 IPF-LFs in culture, when compared to Ctrl-LF, release increased amounts of mtDNA. 34 Furthermore, BALF and serum levels of mtDNA are higher in patients with IPF, as compared to control donors, with serum levels being predictive of all-cause mortality.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

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et al. 2018

J Cellular Molecular Medi

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Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF‐LFs). Primary cultures of IPF‐LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐LFs). Furthermore, IPF‐LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF‐LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐LFs, but not IPF‐LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF‐LF senescence and/or attenuated pharmacologically induced Ctrl‐LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto‐amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

Read

et al. 2018

J Cellular Molecular Medi

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“…TSPO is involved in various complex cellular processes such as intracellular transportation, mitophagy, and apoptosis [95–97]. Among them, mitochondrial dysregulation and especially mitophagy represent a key player of signaling pathways relevant to remodeling in chronic remodeling lung pathologies like asthma [98] and COPD [99]. Quantitative analysis of the acquired emission TSPO PET data is in consonance with these findings where mean tracer uptake, objectified by plateau tissue/plasma, was higher in COPD patients and asthmatics than in healthy volunteers.…”

Section: Tspo Pet Imaging Of Psidsmentioning

confidence: 99%

TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

Largeau

Dupont

Guilloteau

et al. 2017

Contrast Media & Molecular Imaging

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Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatory foci are crucial for an adequate care for patients. In brain diseases, in vivo positron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the field of TSPO PET imaging in PSIDs. Promising preliminary results have been reported in bowel, cardiovascular, and rheumatic inflammatory diseases, consolidated by preclinical studies. Limitations of TSPO PET imaging in PSIDs, regarding both its large expression in healthy peripheral tissues, unlike in central nervous system, and the production of peripheral radiolabeled metabolites, are also discussed, regarding their possible consequences on TSPO PET signal's quantification.

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From Physiological Redox Signalling to Oxidant Stress

Ward

2017

Advances in Experimental Medicine and Biology

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Oxidant stress is strongly associated with cardiovascular disease, including pulmonary hypertension, but antioxidant therapies have so far proven ineffective. This is partly due to a lack of understanding of the key role played by reactive oxygen species (ROS) in physiological cell signalling, and partly to the complex interrelationships between generators of ROS (e.g. mitochondria and NADPH oxidases, NOX), cellular antioxidant systems and indeed Ca signalling. At physiological levels ROS reversibly affect the function of numerous enzymes and transcription factors, most often via oxidation of specific protein thiols. Importantly, they also affect pathways that promote ROS generation by NOX or mitochondria (ROS-induced ROS release), which has an inherent propensity for positive feedback and uncontrolled oxidant production. The reason this does not occur under normal conditions reflects in part a high level of compartmentalisation of ROS signalling within the cell, akin to that for Ca. This article considers the physiological processes which regulate NOX and mitochondrial ROS production and degradation and their interactions with each other and Ca signalling pathways, and discusses how loss of spatiotemporal constraints and activation of positive feedback pathways may impact on their dysregulation in pulmonary hypertension.

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Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander?

Cited by 35 publications

References 138 publications

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

TSPO PET Imaging: From Microglial Activation to Peripheral Sterile Inflammatory Diseases?

From Physiological Redox Signalling to Oxidant Stress

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