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Sub-lethal apoptotic stress enables mtDNA release during senescence and drives the SASP

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196610 | GEO | 2023/08/16

REPOSITORIES: GEO

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Investigating the role of Bax/Bak as a driver of inflammation in aging

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.

2023-08-16 | GSE235225 | GEO

Mitochondrial outer membrane integrity regulates a ubiquitin-dependent NF-kB inflammatory response

Project description:Mitochondria are often essential for apoptosis through mitochondrial outer membrane permeabilization (MOMP). This central event enables cytochrome c release leading to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory, for instance, causing mitochondrial DNA-dependent activation of cGAS-STING signalling. Alongside having emerging functions in health and disease, MOMP associated inflammation can also elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell counteracts this remain poorly defined. Here, we find that upon MOMP, mitochondria are ubiquitylated in a promiscuous manner targeting proteins localised to both inner and outer mitochondrial membranes. Mitochondrial ubiquitylation serves to recruit the essential adaptor molecule, NEMO, leading to activation of pro-inflammatory NF-kB signalling. We find that disruption of mitochondrial outer membrane integrity through different means leads to engagement of a similar pro-inflammatory signalling platform. Thus, mitochondrial integrity directly controls inflammation, whereby permeabilised mitochondria initiate NF-?B signalling. This may be important for the various pathophysiological functions of MOMP-associated inflammation.

2023-12-15 | PXD040192 | Pride

Evaluation of the secretome of senescent melanoma cells and the impact of silencing Mfn1 on the senescence-associated secretory phenotype (SASP) by shotgun proteomics analysis.

Project description:Cellular senescence is a therapy endpoint in melanoma, and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and an enhanced mitochondrial energy metabolism supports resistance to therapy in melanoma. In a previous report we showed that in melanoma, senescence induced by the DNA methylating agent temozolomide, increases fusion proteins mitofusins 1 and 2. Silencing Mfn1 or Mfn2 expression reduced interleukin-6 secretion by senescent cells. Here we expanded these observations evaluating the secretome of senescent melanoma cells using shotgun proteomics, and explored the impact of silencing Mfn1 on the SASP. A significant increase in proteins reported to reduce the immune response towards the tumor was found in the media of senescent cells. The secretion of several of these immunomodulatory proteins was affected by Mfn1 silencing, among them was galectin-9. In agreement, tumors lacking mitofusin 1 responded better to treatment with the methylating agent dacarbazine, tumor size was reduced and a higher immune cell infiltration was detected in the tumor. Our results highlight mitochondrial dynamic proteins as potential pharmacological targets to modulate the SASP in the context of melanoma treatment.

2024-01-26 | PXD043779 | Pride

Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype

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2024-03-30 | GSE247045 | GEO

Unique human beta-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors

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2021-03-18 | GSE162521 | GEO

Mettl14-driven senescence-associated secretory phenotype (SASP) facilitates somatic reprogramming

Project description:The METTL3-METTL14 complex, as the "writer" of N6-methyladenosine (m6A), plays an important role in many biological processes. Previous studies have shown that overexpression of Mettl3 can increase the level of m6A and promotes somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase (MTase) complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in m6A independent manner. Cooperating with Oct4, Sox2, Klf4 and c-Myc (OSKM), Mettl14 transiently increased the senescence-associated secretory phenotype (SASP) gene expression in the non-reprogramming cells at the late reprogramming stage. The conditional medium in reprogramming intermediates overexpressing Mettl4 or its mutant could enhanced the reprogramming, so do IL-6, a component of SASP. Corespondingly, blocking of SASP using senolytic agent or NF-κB inhibitor impairs the effect of Mettl14 on reprogramming. . Our work highlights the m6A independent function of Mettl14 and provides new insight into the interplay between senescence and reprogramming in vitro.

2022-08-24 | GSE196475 | GEO

Genome-wide transcript profiling of human prostate stromal cells in response to genotoxic treatment and SASP inhibitors

Project description:Cancer develops in a complex environment that encompasses a wide spectrum of benign cell types, while the local microenvironment reduces the efficacy of multiple forms of cancer therapies. The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in cellular senescence and the senescence-associated secretory phenotype (SASP), the side effects of the latter frequently fueling advanced pathologies particularly therapeutic resistance. However, candidate approaches to prevent or circumvent the SASP development remains limited. We treated PSC27, a primary normal human prostate stromal cell line, with the genoxotic agents hereby represented by bleomycin, to investigate the relevant mechanisms. In order to control the SASP development, a group of potential SASP inhibitors were applied including p38MAPK, mTOR and TAK1 suppressors. The purpose was to compare the efficacy and effectiveness of these chemicals in combinatin with typical anticancer drugs in minimizing the secretory phenotype upon DNA damage that functionally remodels human stromal cells.

2018-12-27 | GSE90866 | GEO

NAD+ metabolism governs proinflammatory senescence secretome

Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.

2019-03-14 | GSE111841 | GEO

Transcriptomic analysis of senescent cells upon knockdown of 38 candidate SASP-specific regulators.

Project description:IMR90 ER:RAS cells were transfected with scramble siRNA or 2 deconvoluted siRNAs targeting each of 38 candidate genes or positive control siRNAs targeting the senescence regulators p16 and p53 and the SASP regulators NF-kappaB, p38alpha and CEBPbeta. The next day the cells were treated with 4OHT to induce senescence. 6 days later the cells were collected for total mRNA analysis. Our previous experiments had shown that these 38 genes regulate the secretome of senescent cells without affecting other senescence phenotypes such as the growth arrest. By performing RNA-seq we confirmed that knockdown of these genes affected the expression of multiple pro-inflammatory factors in senescence. More importantly, the secreted factors were differentially regulated across the different knockdown conditions indicating potential for specific manipulation of immune response genes.

2018-06-25 | GSE101766 | GEO

RNA-seq analysis of apoptotic HCT116 cells shows widespread mRNA decay and limited noncoding RNA decay.

Project description:Rapid and widespread mRNA decay is a previously unappreciated feature of apoptosis. Previous work showed that apoptotic mRNA decay depends on mitochondrial outer membrane permeabilization (MOMP) and the RNA-processing enzymes, TUT4, TUT7, and DIS3L2. Which RNAs are decayed, however, was not known. Here we present RNA-seq data of TRAIL-induced apoptosis in HCT116 cells showing global decay of mRNAs as well as polyadenylated noncoding RNAs, beginning at the 3’-end.

2018-05-01 | GSE104602 | GEO

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