Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mitochondrial cristae architecture protects against mtDNA release and inflammation

ABSTRACT: Mitochondrial damage causes mtDNA release to activate type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here we performed a mitochondria-targeted CRISPR-knockout screen for regulators of the IFN-I response. Strikingly, our screen revealed dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, MICOS, SAM, MIB, PHB, and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induced mtDNA release and STING-dependent IFN-I response. Furthermore, robust STING-dependent IFN-I response was induced in vivo by knocking out MTX2, a subunit of the SAM complex whose null-mutations cause progeria in human. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE216499 | GEO | 2022/10/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitochondrial cristae architecture protects against mtDNA release and inflammation

Project description:Mitochondrial cristae architecture protects against mtDNA release and inflammation

| PRJNA894105 | ENA

Mitochondrial integrity regulated by FABP5 is a cell-intrinsic checkpoint for Treg suppressive function

Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.

2019-12-26 | GSE126245 | GEO

SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization

Project description:M1 macrophage polarization is modulated by the release of mitochondrial DNA (mtDNA) and subsequent its inflammatory response is augmented by production of mitochondrial reactive oxygen species (mtROS). The pyrimidine-transporting carrier SLC25A33 is located in the mitochondrial inner membrane and has been linked to mtDNA synthesis, but the role of SLC25A33 in inflammatory response of M1 macrophage remains unclear. Here, we elucidate the regulatory mechanisms responsible for up-regulation of SLC25A33 during M1 macrophage polarization and SLC25A33-mediated mtROS production and inflammatory response. Our findings reveal that expression of SLC25A33 was significantly elevated in CD14+ monocytes derived from a patient with sepsis and LPS/IFN-γ-stimulated PMs. We demonstrate that SLC25A33 is upregulated by ATF4 through the MyD88-PI3K-mTORC1 pathway in LPS/IFN-γ-stimulated PMs. Furthermore, SLC25A33 enhanced mtDNA synthesis and its release into the cytosol, facilitated by mtROS-mediated VDAC oligomer formation, thereby contributing to activation of the cGAS-STING inflammatory pathway. Conversely, SLC25A33 knockdown and pyridoxal 5'-phosphate treatment mitigate mtDNA release and reduce M1 polarization and associated inflammatory responses. These findings were consistent across in vitro and in vivo sepsis models, as well as in septic patients with liver abscess. Our findings underscore the significant role of SLC25A33 in inflammation, suggesting that targeting of SLC25A33 could represent a promising therapeutic strategy for managing M1 macrophage-mediated inflammatory diseases, including sepsis.

2024-10-28 | GSE280094 | GEO

Complex regulation of mitochondrial signaling by human adenovirus

Project description:The controlled release of mitochondrial content has emerged as a key step in mitochondrial signaling. Particularly the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-β) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) induces the release of mtDNA in infected cells. The release of mtDNA is mediated by the viral internal minor capsid protein pVI, which localizes into mitochondria and undergoes mitochondria-specific proteolytic processing. The membrane lytic activity of the pVI and the presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release. Surprisingly, the pVI-mediate mtDNA release did not increase but blocked IFN-β gene expression. This inhibition was due to the concurrent leakage of the mitochondrial chaperon protein HSP60, which by inhibiting phosphorylation of the interferon regulatory factor 3 (IRF3), blocked IFN-β gene expression. Collectively, our study suggests that the complex release of mtDNA and mitochondrial proteins modulate the IFN-β signaling cascade during pathogenic HAdV-C5 infection.

2024-05-27 | PXD043440 | Pride

Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA

Project description:Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm. To understand what metabolism-related gene expression changes are altered in mice overexpressing a mitochondrial OGG1 enzyme. Hippocampi tissues were collected from 13 month old control and transgenic mouse and subjected to RNA isolation.

2023-06-14 | GSE227426 | GEO

Cellular pyrimdine imbalance triggers mitochondrial DNA-dependent innate immunity [Scr_vs_Yme1l-si_RNA-seq]

Project description:Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP syn- thase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflamma- tion in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

2021-02-26 | GSE161734 | GEO

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [HeLa_CAD_RNA-seq]

2021-02-26 | GSE161733 | GEO

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [A33_OE_RNA-seq]

2021-02-26 | GSE161732 | GEO

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [WT_vs_Yme1lKO_MEF_RNA-seq]

2021-02-26 | GSE161735 | GEO

YME1L1 KnockOut MEF Cells Whole Proteomics

Project description:Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remained enigmatic. We found that mtDNA-dependent immune signaling via the cGAS-STING pathway is under metabolic control and induced by cellular nucleotide deficiency. The mitochondrial protease YME1L preserves nucleotide pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33, limiting mitochondrial nucleotide import and accumulation of mtDNA. Deficiency of YME1L or the mitochondrial transcription factor A (TFAM) drives an mtDNA-dependent inflammatory response, which depends on SLC25A33 and is suppressed upon replenishment of cellular nucleotide pools. Metabolic insults that deplete cytosolic nucleotides trigger mtDNA-dependent immune responses. Our results thus identify mtDNA release and innate immune signaling as a metabolic response, offering new therapeutic opportunities in disease.

2021-04-27 | PXD018097 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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