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

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 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.

ORGANISM(S): Mus

PROVIDER: GSE235225 | GEO | 2023/08/16

REPOSITORIES: GEO

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

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

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

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

Project description:Bacterial genotoxins can damage host cells by targeting their chromosomal DNA. Salmonella Typhi the causative pathogen of typhoid fever in humans, secretes an essential genotoxin called typhoid toxin, which can induce cellular senescence. Here we show that typhoid toxin triggers the senescence-associated secretory phenotype (SASP) by disrupting mitochondrial function, including a decrease in mitochondrial DNA (mtDNA) content and a disturbance of redox homeostasis within mitochondria. This disruption causes the release of mtDNA into the cytosol, which activates type I interferon via the cGAS-STING pathway. We also demonstrate that the GCN2-mediated integrated stress response modulates the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect to CD4 T cells, potentially leading to senescence in these cells. Our research provides a novel insight into how bacterial genotoxins target mitochondria to induce a proinflammatory SASP, which could be a promising therapeutic target for an anti-toxin intervention.

2024-03-30 | GSE247045 | GEO

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

Project description:Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.

2022-10-01 | GSE186088 | 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

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

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

MLL1 is essential for the senescence-associated secretory phenotype [RNA-Seq]

Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢ÂÂSASP-likeÃ¢ÂÂ inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study consists of a single replicate of RNA-seq from oncogene-induced senescent (or control) IMR90 cells in a MLL1 knockdown (or WT) background, for a total of four samples

2016-02-23 | E-GEOD-78138 | biostudies-arrayexpress

Covalent Inhibition of Pro-Apoptotic BAX

Project description:BCL-2-associated X protein (BAX) is a promising therapeutic target for activating or restraining apoptosis in diseases of pathologic cell survival or cell death, respectively. In response to cellular stress, BAX transforms from a quiescent cytosolic monomer into a toxic oligomer that permeabilizes the mitochondria, releasing key apoptogenic factors. The mitochondrial lipid trans-2-hexadecenal (t-2-hex) sensitizes BAX activation by covalent derivatization of cysteine 126 (C126). Here, we performed a disulfide tethering screen to discover C126-reactive molecules that modulate BAX activity. We identified covalent BAX inhibitor 1 (CBI1) as a compound that selectively derivatizes BAX at C126 and inhibits BAX activation by the physiologic ligand tBID and point mutagenesis. Biochemical and structural analyses revealed that CBI1 can inhibit BAX by a dual mechanism of action: conformational constraint and competitive blockade of lipidation. Hydrogen deuterium exchange mass spectrometry (HDX MS) showed that CBI1 derivatization of BAX C126 reversed the conformational changes caused by the auto-activating mutant F116A These data inform a pharmacologic strategy for blocking apoptosis in diseases of unwanted cell death by covalent targeting of BAX C126.

2024-01-19 | PXD040917 | Pride

Low-dose quercetin positively regulates mouse healthspan

Project description:we reported for the first time a geroprotective effect of low-dose quercetin alone that improved the healthspan of aged C57BL/6J male mice. Que-treated mice showed less hair loss, greater athletic endurance, enhanced diastolic function, and less muscle fibrosis, as well as alleviated cellular senescence in multiple tissues. Interestingly, these changes appear to be rarely associated with transcriptional alterations of protein-coding genes but are linked to heterochromatin stabilization and RTE silencing. Que treatment prevented L1 from hyperactivation, thereby inhibiting SASP.

2019-06-04 | GSE132129 | GEO

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