Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes

ABSTRACT: Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224583 | GEO | 2023/03/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes

Project description:Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.

2023-02-05 | MSV000091206 | MassIVE

Gene expression changes in response to aging compared to heat stress, oxidative stress and ionizing radiation in Drosophila melanogaster

Project description:Gene expression changes in response to aging, hyperoxia, hydrogen peroxide, ionizing radiation, and heat stress were compared using microarrays. While aging shared features with each stress, aging was more similar to the stresses most associated with oxidative stress (hydrogen peroxide, hyperoxia, ionizing radiation) than to heat stress. Aging is associated with down-regulation of numerous mitochondrial genes, including electron-transport-chain (ETC) genes and mitochondrial metabolism genes, and a sub-set of these changes was also observed upon hydrogen peroxide stress and ionizing radiation stress. Aging shared the largest number of gene expression changes with hyperoxia. The extensive down-regulation of mitochondrial and ETC genes during aging is consistent with an aging-associated failure in mitochondrial maintenance, which may underlie the oxidative stress-like and proteotoxic stress-like responses observed during aging. Thirty five sample of RNA including Stress Controls (4 replicates), Heat Stress (3 replicates), Ionizing Radiation (4 replicates), Sugar (4 replicates), Hydrogen Peroxide (4 replicates), Young Controls (6 replicates) , Hyperoxia (6 replicates) and Old (4 replicates) adult Drosophila were analysed by Affymetrix microarrays. Stress Controls were used as controls for Heat Stress, Ionizing Radiation, Sugar and Hydrogen Peroxide samples. Young Controls were used as controls for Hyperoxia and Old samples. All flies were male progeny of a cross between Oregon-R wildtype and transgenic strain w[1118];P{w+ rtTA}(3)[E2]/ TM3. Flies lacking the balancer but bearing the transgene were used.

2012-11-19 | E-GEOD-42255 | biostudies-arrayexpress

Ndufs4-knockout mouse with mitochondria complex I inhibitor treatment

Project description:Glucose hypometabolism is one of the major characteristics of Alzheimer's disease (AD). The energy deficiency in AD brain has been at least partially attributed to accelerated mitochondrial dysfunction than normal aging. In earlier publications, we have shown that small molecule mitochondrial complex I inhibitor CP2 facilitated mitochondrial regeneration and rescued mitochondrial deficiency in familial AD mice model APP-PS1. Here in this study, we investigated whether a typical mitochondrial deficiency mouse model could recapitulate molecular expression signatures of AD brain and whether CP2 was able to rescue the AD brain phenotype. Ndufs4 is one of the regulatory subunits of mitochondria complex I. Knockout of Ndufs4 resulted in complex I assembly failure and approximately half mitochondrial function loss. Ndufs4-knockout mice are viable but are short in lifespan (up to about 90 days). This model has been previously used to study Leigh syndrome, a heritable mitochondrial deficiency disease. In this dataset, we performed RNAseq on brains of CP2 treated Ndufs4-knockout mice and examined the expression changes upon CP2 treatment.

2023-12-01 | GSE242286 | GEO

Gene expression changes in response to aging compared to heat stress, oxidative stress and ionizing radiation in Drosophila melanogaster

2012-11-19 | GSE42255 | GEO

Transcriptome Analysis Reveals Gene Expression Changes in a mouse Model of Hyperoxia-induced acute lung injury

Project description:Oxygen therapy is essential for cure critically patients in ICU, but hyperoxia can cause damage to many organs, including the lungs, leading to Hyperoxia Acute Lung Injury (HALI), a mild type of acute respiratory distress syndrome (ARDS). However, the comprehensive pathogenesis and regulation mechanisms underlying the development of HALI remain unclear. In this study, we conducted a mouse model with hyperoxia treatment and sequenced the gene expression pattern of HALI-mice and relative control (RNA-seq).

2024-04-05 | GSE237260 | GEO

In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Novel Mediator of the Hyperoxia Response

Project description:Oxygen deprivation and excess are both toxic to mammals. Thus, the body’s ability to adapt to varying oxygen tensions is critical for survival. While the transcriptional response to acute hypoxia has been well-studied, the post-translational effects of hypoxia and hyperoxia have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to changes in oxygen tension, likely due to the direct exposure of alveoli to inhaled oxygen. In particular, several extracellular matrix (ECM) proteins such as collagens and laminins, are stabilized in the lung under both hypoxia and hyperoxia, suggesting their post-translational regulation. Furthermore, we validate our previous finding that complex 1 of the electron transport chain (ETC) is destabilized in hyperoxia, explaining the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a novel transcriptional regulator in hyperoxic lung, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of the effects of oxygen tensions on protein turnover rates and identifies novel tissue-specific mediators of oxygen-dependent responses.

2023-12-10 | GSE234123 | GEO

In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Novel Mediator of the Hyperoxia Response

Project description:Oxygen deprivation and excess are both toxic to mammals. Thus, the ability to adapt to varying oxygen tensions is critical for survival. While the transcriptional response to acute hypoxia has been well-studied, the post-translational effects of hypoxia and hyperoxia have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to changes in oxygen tension, likely due to the direct exposure of alveoli to inhaled oxygen. In particular, several extracellular matrix (ECM) proteins such as collagens and laminins, are stabilized in the lung under both hypoxia and hyperoxia, suggesting their post-translational regulation. Furthermore, we validate our previous finding that complex 1 of the electron transport chain (ETC) is destabilized in hyperoxia, explaining the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a novel transcriptional regulator in hyperoxic lung, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of the effects of oxygen tensions on protein turnover rates and identifies novel tissue-specific mediators of oxygen-dependent responses.

2023-06-04 | MSV000092095 | MassIVE

Affymetrix array of postnatal day 4 mouse atria exposed to room air or hyperoxia

Project description:It is unclear why preterm birth increases risk of cardiovascular disease later in life. Studies in mice indicate excess oxygen typically used to treat preterm infants causes pulmonary hypertension, cardiac failure, and shortens lifespan. We previously reported neonatal hyperoxia causes pulmonary hypertension in aged mice as defined pathologically by pulmonary capillary rarefaction, dilation of pulmonary arterioles and veins, right ventricular hypertrophy, and reduced lifespan. These changes were preceded by a pronounced growth inhibition of cardiomyocytes lining the pulmonary vein and extending into the left atria, resulting in diastolic heart failure as the mice aged. To identify transcriptional changes by which hyperoxia suppresses proliferation of these cardiomyocytes, newborn mice were exposed to room air or 100% oxygen between birth and postnatal day 4. RNA was then isolated from atria of 3 room air and 4 hyperoxia-exposed mice and used to probe Affymetrix mouse array 430 versus 2.0

2021-02-23 | E-MTAB-9008 | biostudies-arrayexpress

Murine podocyte mitochondrial complexsome analysis

Project description:Proximity labeling discovered a few mitochondrial cristae organizing proteins as NDUFS4 interacting protein. However proximity labeling is unable to differentiate between a direct interaction or a mere close association between NDUFS4 and cristae forming proteins. Additionally, it does not specify if the association of NDUFS4 with these proteins occurs in the context of individual complexes or RSCs. Consequently, to explore whether these cristae forming proteins comigrate and are retained within different complexes in RSCs, we performed complexsome profiling analysis on isolated mitochondria from HG-treated Ndufs4 overexpressed podocytes, with HG-treated cells as control. We separated ETC complexes with BN-PAGE, sliced five distinct bands representing distinct RSCs, labeled 1–5, after Coomassie blue staining, followed by mass spectrometry (LC-MS/MS).

2024-02-08 | PXD041203 | Pride

Relative quantification of proteins in wild-type vs NDUFS4 -/- in mouse kidney mitochondrial membranes

Project description:Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of mouse-heart ndufs4-/- complex I revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12 (that replaces its paralogue NDUFAF2 in mature complex I) is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free but otherwise complete enzyme. We propose NDUFAF2 as the major recruiter of the NADH-dehydrogenase module during assembly of the complex. Our results provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

2024-01-02 | PXD044975 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data