bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2022‒12‒25
eight papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. Pathogens. 2022 Nov 23. pii: 1400. [Epub ahead of print]11(12):
      Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics.
    Keywords:  ALRs; CLRs; NLRs; PANoptosis; PANoptosome; RIG-I; RLRs; RNA virus; TLRs; apoptosis; caspase; cell death; ebolavirus; filovirus; host–pathogen interactions; inflammasome; inflammation; innate immunity; interferon; marburgvirus; necroptosis; pattern recognition receptors; pyroptosis
  2. Front Pharmacol. 2022 ;13 1033982
      The cyclic GMP-AMP synthase-stimulator of interferon genes signal transduction pathway is critical in innate immunity, infection, and inflammation. In response to pathogenic microbial infections and other conditions, cyclic GMP-AMP synthase (cGAS) recognizes abnormal DNA and initiates a downstream type I interferon response. This paper reviews the pathogenic mechanisms of stimulator of interferon genes (STING) in different organs, including changes in fibrosis-related biomarkers, intending to systematically investigate the effect of the cyclic GMP-AMP synthase-stimulator of interferon genes signal transduction in inflammation and fibrosis processes. The effects of stimulator of interferon genes in related auto-inflammatory and neurodegenerative diseases are described in this article, in addition to the application of stimulator of interferon genes-related drugs in treating fibrosis.
    Keywords:  cyclic GMP-AMP synthase-stimulator of interferon genes signaling pathway; inflammation; innate immunity; organ fibrosis; remodeling
  3. Curr Opin Neurobiol. 2022 Dec 16. pii: S0959-4388(22)00158-1. [Epub ahead of print]78 102664
      Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (aSyn) in the nigrostriatal pathway that is followed by severe neuroinflammatory response. PD etiology is still puzzling; however, the mitocentric view might explain the vast majority of molecular findings not only in the brain, but also at systemic level. While neuronal degeneration is tightly associated with mitochondrial dysfunction, the causal role between aSyn accumulation and mitochondrial dysfunction still requires further investigation. Moreover, mitochondrial dysfunction can elicit an inflammatory response that may be transmitted locally but also in a long range through systemic circulation. Furthermore, mitochondrial-driven innate immune activation may involve the synthesis of antimicrobial peptides, of which aSyn poses as a good candidate. While there is still a need to clarify disease-elicited mechanisms and how aSyn has the ability to modulate mitochondrial and cellular dysfunction, recent studies provide insightful views on mitochondria-inflammation axis in PD etiology.
  4. Nat Rev Mol Cell Biol. 2022 Dec 21.
      Regulated cell death (RCD) relies on activation and recruitment of pore-forming proteins (PFPs) that function as executioners of specific cell death pathways: apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK) for apoptosis, gasdermins (GSDMs) for pyroptosis and mixed lineage kinase domain-like protein (MLKL) for necroptosis. Inactive precursors of PFPs are converted into pore-forming entities through activation, membrane recruitment, membrane insertion and oligomerization. These mechanisms involve protein-protein and protein-lipid interactions, proteolytic processing and phosphorylation. In this Review, we discuss the structural rearrangements incurred by RCD-related PFPs and describe the mechanisms that manifest conversion from autoinhibited to membrane-embedded molecular states. We further discuss the formation and maturation of membrane pores formed by BAX/BAK/BOK, GSDMs and MLKL, leading to diverse pore architectures. Lastly, we highlight commonalities and differences of PFP mechanisms involving BAX/BAK/BOK, GSDMs and MLKL and conclude with a discussion on how, in a population of challenged cells, the coexistence of cell death modalities may have profound physiological and pathophysiological implications.
  5. STAR Protoc. 2022 Dec 20. pii: S2666-1667(22)00838-3. [Epub ahead of print]4(1): 101958
      Current approaches, such as fixed-cell imaging or single-snapshot imaging, are insufficient to capture cytoskeleton-mediated mitochondrial fission. Here, we present a protocol to capture actin-mediated mitochondrial fission using high-resolution time-lapse imaging. We describe steps starting from cell preparation and mitochondria labeling through to live-cell imaging and final analysis. This approach is also applicable for analysis of multiple cytoskeleton-mediated organelle events such as vesicle trafficking, membrane fusion, and endocytic events in live cells. For complete details on the use and execution of this protocol, please refer to Shimura et al. (2021).1.
    Keywords:  Cell Biology; Microscopy; Molecular Biology
  6. Nature. 2022 Dec 21.
      R-loops are RNA-DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2-4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA-DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA-DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. 5-7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. 8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. 9) and in BRCA1-mutated cancer cells10. These findings establish RNA-DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.
  7. Sci Signal. 2022 Dec 20. 15(765): eabo4356
      Histone deacetylases (HDACs) play important roles in immunity and inflammation. Through functional screening, we identified HDAC10 as an inhibitor of the type I interferon (IFN) response mediated by interferon regulatory factor 3 (IRF3). HDAC10 abundance was decreased in mouse macrophages in response to innate immune stimuli and was reduced in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) compared with that in PBMCs from healthy donors. Deficiency in HDAC10 in mouse embryonic fibroblasts and in mice promoted the expression of genes encoding type I IFNs and of IFN-stimulated genes (ISGs), leading to enhanced antiviral responses in vitro and in vivo. HDAC10 bound in a deacetylase-independent manner to IRF3 in uninfected cells to inhibit the phosphorylation of IRF3 at Ser396 by TANK-binding kinase 1 (TBK1). Upon viral infection, HDAC10 was targeted for autophagy-mediated degradation through its interaction with LC3-II. Consequently, IRF3 phosphorylation was increased, which resulted in enhanced type I IFN production and antiviral responses. Our findings identify a potential target for improving host defense responses against pathogen infection and for treating autoimmune disease.
  8. Differentiation. 2022 Dec 06. pii: S0301-4681(22)00090-1. [Epub ahead of print]130 7-15
      Fibroblast growth factors (Fgfs) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of Fgf8 in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the Fgf8 mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of Bak and Bax abrogates normal cell death and has minimal effect on renal development. However, in Fgf8 mutants, the combined loss of Bak and Bax rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in Fgf8 mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK/BAX and for subsequent steps involving, as yet, undefined roles in kidney development.
    Keywords:  Apoptosis; Cell death; Fgf8; Fibroblast growth factor; Kidney