Sub-lethal apoptotic stress enables mtDNA release during senescence and drives the SASP
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ABSTRACT:
PROVIDER: PRJNA806156 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17988712_1.fastq.gz | Fastqsanger.gz | |||
| SRR17988712_2.fastq.gz | Fastqsanger.gz | |||
| SRR17988713_1.fastq.gz | Fastqsanger.gz | |||
| SRR17988713_2.fastq.gz | Fastqsanger.gz | |||
| SRR17988714_1.fastq.gz | Fastqsanger.gz |
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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:Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
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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.
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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.
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Project description:The accumulation of senescent cells contributes to age-related organ degradation and susceptibility to chronic diseases. These cells exhibit the senescence-associated secretory phenotype (SASP), affecting cellular and overall aging. 18β-GA has anti-inflammatory effects。RNA-seq was used to analyze the changes in SASP genes and signaling pathways in senescent cells after 18β-GA treatment. 18β-GA can effectively inhibit the activation of IL6 downstream signaling pathways and reduce the expression of SASP-related genes in senescent cells.
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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 are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die. Here, we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores leading to the 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 in aged mice. Our results reveal, unexpectedly, 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-induced inflammation may be a new therapeutic avenue to improve healthspan.
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