bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023–02–12
eleven papers selected by
Bradley Irizarry, Thomas Jefferson University
  1. Oxidized mitochondrial DNA: a protective signal gone awry.
  2. Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release.
  3. How the Innate Immune DNA Sensing cGAS-STING Pathway Is Involved in Apoptosis.
  4. PRRSV infection activates NLRP3 inflammasome through inducing cytosolic mitochondrial DNA stress.
  5. The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
  6. Inflammation and DNA damage: cause, effect or both.
  7. Non-phosphorylatable mutants of Ser184 lead to incomplete activation of Bax.
  8. Regulation of DNA damage response by trimeric G-proteins.
  9. RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.
  10. How much (evil) intelligence can be encoded by 30 kb?
  11. Association of circulating MtDNA with CVD in hemodialysis patients and in vitro effect of exogenous MtDNA on cardiac microvascular inflammation.
  1. Trends Immunol. 2023 Feb 02. pii: S1471-4906(23)00017-0. [Epub ahead of print]
    Oxidized mitochondrial DNA: a protective signal gone awry.
    Hongxu Xian, Michael Karin.
      Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.
    Keywords:  NLRP3 inflammasome; Ox-mtDNA; autoimmunity; cGAS–STING; cell-free DNA; immunopathology; inflammation; stressed mitochondria
    DOI:  https://doi.org/10.1016/j.it.2023.01.006
  2. PLoS Pathog. 2023 Feb 06. 19(2): e1011132
    Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release.
    Huisheng Liu, Zixiang Zhu, Qiao Xue, Fan Yang, Zongqiang Li, Zhaoning Xue, Weijun Cao, Jijun He, Jianhong Guo, Xiangtao Liu, Andrew E Shaw, Donald P King, Haixue Zheng.
      Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release. The released mtDNA bound to cGAS and activated cGAS-mediated antiviral immune response. cGAS was essential for inhibiting EV-A71, SVV, and FMDV replication by regulation of IFN-β production. cGAS deficiency contributed to higher mortality of EV-A71- or FMDV-infected mice. In addition, we found that SVV 2C protein was responsible for decreasing cGAS expression through the autophagy pathway. The 9th and 153rd amino acid sites in 2C were critical for induction of cGAS degradation. Furthermore, we also show that EV-A71, CA16, and EMCV 2C antagonize the cGAS-stimulator of interferon genes (STING) pathway through interaction with STING, and highly conserved amino acids Y155 and S156 were critical for this inhibitory effect. In conclusion, these data reveal novel mechanisms of picornaviruses to block the antiviral effect mediated by the cGAS-STING signaling pathway, which will provide insights for developing antiviral strategies against picornaviruses.
    DOI:  https://doi.org/10.1371/journal.ppat.1011132
  3. Int J Mol Sci. 2023 Feb 03. pii: 3029. [Epub ahead of print]24(3):
    How the Innate Immune DNA Sensing cGAS-STING Pathway Is Involved in Apoptosis.
    Wanglong Zheng, Anjing Liu, Nengwen Xia, Nanhua Chen, François Meurens, Jianzhong Zhu.
      The cGAS-STING signaling axis can be activated by cytosolic DNA, including both non-self DNA and self DNA. This axis is used by the innate immune system to monitor invading pathogens and/or damage. Increasing evidence has suggested that the cGAS-STING pathway not only facilitates inflammatory responses and the production of type I interferons (IFN), but also activates other cellular processes, such as apoptosis. Recently, many studies have focused on analyzing the mechanisms of apoptosis induced by the cGAS-STING pathway and their consequences. This review gives a detailed account of the interplay between the cGAS-STING pathway and apoptosis. The cGAS-STING pathway can induce apoptosis through ER stress, NLRP3, NF-κB, IRF3, and IFN signals. Conversely, apoptosis can feed back to regulate the cGAS-STING pathway, suppressing it via the activation of caspases or promoting it via mitochondrial DNA (mtDNA) release. Apoptosis mediated by the cGAS-STING pathway plays crucial roles in balancing innate immune responses, resisting infections, and limiting tumor growth.
    Keywords:  DNA sensing; IFN; apoptosis; cGAS-STING; innate immunity
    DOI:  https://doi.org/10.3390/ijms24033029
  4. Vet Microbiol. 2023 Feb 03. pii: S0378-1135(23)00025-1. [Epub ahead of print]279 109673
    PRRSV infection activates NLRP3 inflammasome through inducing cytosolic mitochondrial DNA stress.
    Huawei Li, Xiaotian Yang, Yuzhen Song, Qingguo Zhu, Ziqian Liao, Yixuan Liang, Jianghao Guo, Bo Wan, Dengke Bao.
      Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe interstitial pneumonia and inflammatory response in piglets and growing pigs. IL-1β is implicated in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection. Mitochondria are critical intracellular organelles which is served as signaling platform for antiviral immunity response to participate in immune response of virus infection. The role of mitochondria in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection has not been elucidated. Here, our data suggested that PRRSV infection facilitates mitochondrial dysfunction, which induces cytosolic mitochondrial DNA (mtDNA) stress and ROS accumulation, severally activates the NLRP3 inflammasome and NF-κB signaling pathway, and consequently stimulates IL-1β production in PAMs. Furthermore, mtDNA degradation by DNase I abrogates the activation of NLRP3 inflammasome and IL-1β secretion during PRRSV infection. Scavenging ROS significantly inhibits NF-κB signaling activation and the subsequently transcription and secretion of IL-1β. In conclusion, our results indicate that cytosolic mtDNA stress and ROS accumulation after PRRSV infection-induced mitochondrial dysfunction activate NLRP3 inflammasome and NF-κB signaling pathway to promote IL-1β production, revealing a new strategy for vaccine and drug development to PRRSV.
    Keywords:  IL-1β; Inflammation; PAMs; PRRSV; mtDNA
    DOI:  https://doi.org/10.1016/j.vetmic.2023.109673
  5. Int J Mol Sci. 2023 Jan 27. pii: 2479. [Epub ahead of print]24(3):
    The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
    Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.
      Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.
    Keywords:  diseases; mitochondria; mitochondrial protein import machineries; mitochondrial unfolded protein response; proteins
    DOI:  https://doi.org/10.3390/ijms24032479
  6. Nat Rev Rheumatol. 2023 Feb 07.
    Inflammation and DNA damage: cause, effect or both.
    Antonio Pezone, Fabiola Olivieri, Maria Vittoria Napoli, Antonio Procopio, Enrico Vittorio Avvedimento, Armando Gabrielli.
      Inflammation is a biological response involving immune cells, blood vessels and mediators induced by endogenous and exogenous stimuli, such as pathogens, damaged cells or chemicals. Unresolved (chronic) inflammation is characterized by the secretion of cytokines that maintain inflammation and redox stress. Mitochondrial or nuclear redox imbalance induces DNA damage, which triggers the DNA damage response (DDR) that is orchestrated by ATM and ATR kinases, which modify gene expression and metabolism and, eventually, establish the senescent phenotype. DDR-mediated senescence is induced by the signalling proteins p53, p16 and p21, which arrest the cell cycle in G1 or G2 and promote cytokine secretion, producing the senescence-associated secretory phenotype. Senescence and inflammation phenotypes are intimately associated, but highly heterogeneous because they vary according to the cell type that is involved. The vicious cycle of inflammation, DNA damage and DDR-mediated senescence, along with the constitutive activation of the immune system, is the core of an evolutionarily conserved circuitry, which arrests the cell cycle to reduce the accumulation of mutations generated by DNA replication during redox stress caused by infection or inflammation. Evidence suggests that specific organ dysfunctions in apparently unrelated diseases of autoimmune, rheumatic, degenerative and vascular origins are caused by inflammation resulting from DNA damage-induced senescence.
    DOI:  https://doi.org/10.1038/s41584-022-00905-1
  7. Front Oncol. 2022 ;12 1068994
    Non-phosphorylatable mutants of Ser184 lead to incomplete activation of Bax.
    Lilit Simonyan, Mathilde Gonin, James Hanks, Jordan Friedlein, Kevin Dutrec, Hubert Arokium, Akandé Rouchidane Eyitayo, Toukounou Megann Doudy, Stéphane Chaignepain, Stéphen Manon, Laurent Dejean.
      The S184 residue of Bax is the target of several protein kinases regulating cell fate, including AKT. It is well-established that, in cellulo, the substitution of S184 by a non-phosphorylatable residue stimulates both the mitochondrial localization of Bax, cytochrome c release, and apoptosis. However, in in vitro experiments, substituted mutants did not exhibit any increase in their binding capacity to isolated mitochondria or liposomes. Despite exhibiting a significant increase of the 6A7 epitope exposure, substituted mutants remain limited in their ability to form large oligomers, suggesting that they high capacity to promote apoptosis in cells was more related to a high content than to an increased ability to form large pores in the outer mitochondrial membranes.
    Keywords:  BCL-2 family; apoptosis; bax; conformationnal changes; mitochondria; phosphorylation
    DOI:  https://doi.org/10.3389/fonc.2022.1068994
  8. iScience. 2023 Feb 17. 26(2): 105973
    Regulation of DNA damage response by trimeric G-proteins.
    Amer Ali Abd El-Hafeez, Nina Sun, Anirban Chakraborty, Jason Ear, Suchismita Roy, Pranavi Chamarthi, Navin Rajapakse, Soumita Das, Kathryn E Luker, Tapas K Hazra, Gary D Luker, Pradipta Ghosh.
      Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•βγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the "free" Gβγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.105973
  9. bioRxiv. 2023 Jan 28. pii: 2023.01.27.525911. [Epub ahead of print]
    RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.
    Alexandra U Zezulin, Darwin Ye, Elizabeth Howell, Daniel Yen, Erica Bresciani, Jamie Diemer, Jian-Gang Ren, Mohd Hafiz Ahmad, Lucio H Castilla, Ivo P Touw, Andy J Minn, Wei Tong, P Paul Liu, Kai Tan, Wenbao Yu, Nancy A Speck.
      The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancies (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 regulates inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to restrict the inflammatory response of neutrophils to toll-like receptor 4 (TLR4) signaling. Loss of RUNX1 in GMPs increased the TLR4 coreceptor CD14 on neutrophils, which contributed to neutrophils’ increased inflammatory cytokine production in response to the TLR4 ligand lipopolysaccharide. RUNX1 loss increased the chromatin accessibility of retrotransposons in GMPs and neutrophils and induced a type I interferon signature characterized by enriched footprints for signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRF) in opened chromatin, and increased expression of interferon-stimulated genes. The overproduction of inflammatory cytokines by neutrophils was reversed by inhibitors of type I IFN signaling. We conclude that RUNX1 restrains the chromatin accessibility of retrotransposons in GMPs and neutrophils, and that loss of RUNX1 increases proinflammatory cytokine production by elevating tonic type I interferon signaling.
    DOI:  https://doi.org/10.1101/2023.01.27.525911
  10. Biol Futur. 2023 Feb 08.
    How much (evil) intelligence can be encoded by 30 kb?
    Ernő Duda.
      Genomes of most RNA viruses are rarely larger than the size of an average human gene (10-15 kb) and still code for a number of biologically active polypeptides that modify the immune system and metabolism of the host organism in an amazingly complex way. Prolonged coevolution developed tricks by which viruses can dodge many protective mechanisms of the host and lead to the formation of molecular mimicry patterns. Some viruses inhibit the interferon response, interfere with the membrane destroying effects of the activated complement cascade. They can replicate in cellular compartments formed by inner membranes of the cell hiding their characteristic features from diverse pattern recognition receptors. In many cases-and in this respect, the new coronavirus is a champion-they can exploit our own defensive mechanisms to cause serious harm, severe symptoms and frequently deadly disease.
    Keywords:  Interferon; Molecular mimicry; NETosis; Pyroptosis; RNA viruses; SARS-CoV-2
    DOI:  https://doi.org/10.1007/s42977-023-00153-8
  11. BMC Cardiovasc Disord. 2023 02 08. 23(1): 74
    Association of circulating MtDNA with CVD in hemodialysis patients and in vitro effect of exogenous MtDNA on cardiac microvascular inflammation.
    Zhen Fan, Ya Feng, Li Zang, Yi Guo, Xiao-Yi Zhong.
       BACKGROUND: Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia.
    METHODS: Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and erythrocyte sedimentation rate (ESR) were measured by standard assays. Ten-year CVD risk was calculated from the Framingham risk score (FRS) model. In vitro study, human cardiac microvascular endothelial cells (HCMECs) were incubated with normal or uremic serum, with or without exogenous MtDNA. Intracellular toll-like receptor 9 (TLR9), adhesion molecule 1 (ICAM-1), MCP-1 and tumor necrosis factor-α (TNF-α) and cytosolic MtDNA were detected by qPCR.
    RESULTS: Plasma MtDNA in MHD patients was significantly higher than healthy controls (4.74 vs. 2.41 × 105 copies/mL; p = 0.000). Subsequently, the MHD patients were classified into two groups based on the MtDNA median (4.34 × 105 copies/mL). In stratified analyses, the levels of Hs-CRP (5.02 vs. 3.73 mg/L; p = 0.042) and MCP-l (99.97 vs. 64.72 pg/mL; p = 0.008) and FRS (21.80 vs. 16.52; p = 0.016) in the high plasma MtDNA group were higher than those in the low plasma MtDNA group. In vitro study, we found that exogenous MtDNA aggravated uremic serum-induced microvascular inflammation (ICAM-1 and TNF-α) in HCMECs (all p < 0.05). Besides, the addition of MtDNA to the medium resulted in a further increase in cytosolic MtDNA and TLR9 levels in uremic serum-treated cells (all p < 0.05). In patients with MHD, MtDNA levels in plasma were significantly reduced after a single routine hemodialysis (pre 4.47 vs. post 3.45 × 105 copies/mL; p = 0.001) or hemodiafiltration (pre 4.85 vs. post 4.09 × 105 copies/mL; p = 0.001). These two approaches seem similar in terms of MtDNA clearance rate (21.26% vs. 11.94%; p = 0.172).
    CONCLUSIONS: Overall, the present study suggests that MtDNA released into the circulation under the uremic toxin environment may adversely affect the cardiovascular system by exacerbating microvascular inflammation, and that reducing circulating MtDNA might be a future therapeutic strategy for the prevention of MHD-related CVD.
    Keywords:  Cardiac microvascular endothelial cells; Cardiovascular disease; Inflammation; Maintenance hemodialysis; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12872-023-03104-2
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