Mitochondrial cristae architecture protects against mtDNA release and inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA894105 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22031418_1.fastq.gz | Fastqsanger.gz | |||
| SRR22031418_2.fastq.gz | Fastqsanger.gz | |||
| SRR22031419_1.fastq.gz | Fastqsanger.gz | |||
| SRR22031419_2.fastq.gz | Fastqsanger.gz | |||
| SRR22031420_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 80 |
Similar Datasets
Project description: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.
2022-10-28 | GSE216499 | GEO
Project description:Fumarate induces vesicular release of mtDNA to drive innate immunity
| PRJNA761795 | ENA
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
Project description:Sub-lethal apoptotic stress enables mtDNA release during senescence and drives the SASP
| PRJNA806156 | ENA
Project description:Regulator of chromosome condensation domain-containing protein 1 (RCCD1) plays an important role in chromosome segregation and microtubule stability in the nucleus and has been identified recently as a potential driver for breast cancer. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial inner membrane, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mitochondrial nucleoid organization, thereby influencing mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension in RCCD1 functionality, indicating RCCD1 is an essential regulator of mtDNA dynamics and mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer.
2023-12-01 | GSE219134 | GEO
Project description:Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor a), including expression of specific ESR1 variants is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males, and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.
2024-10-30 | GSE280715 | GEO
Project description:Senescent cells drive age-related tissue dysfunction partially via the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria also control apoptosis, a cell fate generally perceived as distinct from cellular senescence, which is apoptosis resistant. Here, we show that mitochondrial outer membrane permeability (MOMP) occurring in a small subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores and results in release of mitochondrial DNA (mtDNA) into the cytosol, which in turn activates the cGAS/STING pathway, a major regulator of the SASP. Importantly, we found that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan parameters in aged mice. Our results propose the novel concept that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms, and that sub-lethal mitochondrial apoptotic stress is a major driver of the SASP. We also provide proof-of-concept that inhibition of miMOMP may be a new therapeutic avenue to improve healthspan.
2023-08-16 | GSE196610 | GEO
Project description:Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria and mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here, we show that mtDNA damage after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, leads to an exacerbated mtDNA turnover. mtDNA removal depends on lysosomal function and requires the autophagy protein Atg5 but is independent of canonical mitophagy or autophagy. Using proximity labelling, we demonstrated that the area of influence of mitochondrial nucleoids differs upon mtDNA damage, which induces mitochondrial membrane remodelling and endosomal recruitment in close proximity to mitochondrial nucleoid sub compartments. Targeting of nucleoids is controlled by the mitochondrial transmembrane proteins ATAD3 and SAMM50, which together with the endosomal trafficking protein VPS35, orchestrate endosomal nucleoid engulfment. SAMM50 acts as a gatekeeper to avoid mtDNA release to the cytoplasm and facilitating mtDNA transfer to VPS35. Lastly, we show that stimulation of lysosomal activity by rapamycin selectively removes mtDNA deletions in vivo, without affecting mtDNA copy number. With these results, we unveil the molecular players of a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network, a process with multiple potential benefits to understand human mtDNA related diseases, either inherited, acquired or due to normal ageing.
2022-11-07 | PXD023939 | Pride
Project description:Expression analysis of cells the given amount of time after mtDNA was lost (or Nar1 expression was repressed) compared to pretreatment (or NAR1 being fully expressed). One time course experiment (Cells a given amount of time following mtDNA loss compared to cells with intact mtDNA), with 2 two condition experiments (Cells with the ATP1-111 genotype 27 hours following mtDNA loss compared to the same cells with intact mtDNA, and cells 27 hours following repression of NAR1 comared to cells expressing NAR1). Each data point had 3 biological replicates, and was dye-swapped. One replicate per array.
2010-06-21 | E-GEOD-15302 | biostudies-arrayexpress
Project description:Mitochondrial DNA (mtDNA) breaks are toxic 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 poorly understood. We reasoned that factors that sense mtDNA damage are likely to be recruited to nucleoids shortly after break formation, prompting us to develop a proteomic-based approach to survey the interactome of mitochondrial nucleoids. Specifically, we combined proximity-dependent biotin labeling with Stable Isotope Labeling by Amino acids in Cell culture (SILAC) and tandem mass spectrometry. We used mitochondrial targeted restriction enzymes for the proximity probe and show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Notably, mtDNA breaks activate the integrated stress response (ISR) through phosphorylation of eIF2a by the OMA1-DELE1-HRI pathway. Inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, hinting at a role for the ISR in mitigating mitochondrial dysfunction following mtDNA damage. Electron microscopy reveals defective mitochondrial membranes and cristae ultrastructure. Last, we highlight a potential role for ATAD3A - a protein that is anchored to the inner mitochondrial membrane while interacting with nucleoids - in relaying the signal from damaged mtDNA to the mitochondrial inner membrane. Altogether, our study delineates the sequence of events linking damaged mitochondrial genomes to the cytoplasmic stress response. The mass spectrometry raw files for the combined SILAC and proximity-dependent biotin labeling experiment are deposited here.
2022-10-05 | MSV000090459 | MassIVE