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

Similar Datasets

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

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 pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [WT_vs_Yme1lKO_MEF_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 | GSE161735 | GEO

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

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

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

Nerv. System Specific Yme1l KO (NYKO) Mice Retina Samples (30-31wks old)

Project description:Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. We found that mtDNA-dependent immune signalling 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 transport and accumulation of mtDNA. Deficiency of YME1L or of 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. Depletion of cytosolic nucleotides upon starvation or downregulation of de novo nucleotide synthesis triggers mtDNA-dependent immune responses. Our results thus identify mtDNA release and innate immune signalling as a metabolic response, offering new therapeutic opportunities in disease.

2021-04-27 | PXD019849 | Pride

Effect of Rh(III) on gene expression in HeLa cell line

Project description:We designed a highly emissive rhodium(III) complex ( Rh(III) complex) as the mtDNA intercalator. Rh(III) complex can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh(III) complex activates the mitochondrial retrograde signaling by disturbing the key metabolites. Herein,we performed RNA-seq to illustrate the function of Rh(III) complex on HeLa cells. RNA-seq was performed on HeLa cells, which were treated by 1% DMSO or Rh(III) complex (1 uM, 6h), respectively.

2023-07-06 | GSE221227 | GEO

mtDNA breaks compromise mitochondrial membrane ultrastructure and trigger an integrated stress response

Project description:Mitochondrial DNA (mtDNA) breaks are deleterious lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain ill-defined. Using mitochondrial targeted restriction enzymes, we show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Furthermore, mtDNA damage activates the integrated stress response (ISR) through phosphorylation of eIF2α by the OMA1-DELE1-HRI pathway. Electron microscopy reveals concomitant defects in mitochondrial membranes and cristae ultrastructure. Notably, inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, thereby implicating this stress response in mitigating mitochondrial dysfunction following mtDNA damage. Last, we provide evidence suggesting that ATAD3A, a membrane-anchored protein that interacts with nucleoids, relays the signal from mtDNA breaks to the inner mitochondrial membrane. Altogether, our study fully delineates the sequence of events linking damaged mitochondrial genomes with the cytoplasm and uncovers an unanticipated role for the ISR in response to mitochondrial genome instability.

2022-10-04 | GSE214512 | GEO

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