bims-mitper Biomed News
on Mitochondrial Permeabilization
Issue of 2023‒03‒19
eleven papers selected by
Bradley Irizarry
Thomas Jefferson University

  1. Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00124-7. [Epub ahead of print]83(6): 843-856
      Mitochondria are cellular organelles with a major role in many cellular processes, including not only energy production, metabolism, and calcium homeostasis but also regulated cell death and innate immunity. Their proteobacterial origin makes them a rich source of potent immune agonists, normally hidden within the mitochondrial membrane barriers. Alteration of mitochondrial permeability through mitochondrial pores thus provides efficient mechanisms not only to communicate mitochondrial stress to the cell but also as a key event in the integration of cellular responses. In this regard, eukaryotic cells have developed diverse signaling networks that sense and respond to the release of mitochondrial components into the cytosol and play a key role in controlling cell death and inflammatory pathways. Modulating pore formation at mitochondria through direct or indirect mechanisms may thus open new opportunities for therapy. In this review, we discuss the current understanding of the structure and molecular mechanisms of mitochondrial pores and how they function at the interface between cell death and inflammatory signaling to regulate cellular outcomes.
    Keywords:  BAK; BAX; VDAC; apoptosis; gasdermin; inflammation; mPTP; membrane pore
  2. Nat Commun. 2023 Mar 14. 14(1): 1399
      During apoptosis, mitochondrial outer membrane permeabilization (MOMP) enables certain mitochondrial matrix macromolecules to escape into the cytosol. However, the fate of mitochondrial RNA (mtRNA) during apoptosis is unknown. Here, we demonstrate that MOMP results in the cytoplasmic release of mtRNA and that executioner caspases-3 and -7 (casp3/7) prevent cytoplasmic mtRNA from triggering inflammatory signaling. In the setting of genetic or pharmacological casp3/7 inhibition, apoptotic insults result in mtRNA activation of the MDA5/MAVS/IRF3 pathway to drive Type I interferon (IFN) signaling. This pathway is sufficient to activate tumor-intrinsic Type I IFN signaling in immunologically cold cancer models that lack an intact cGAS/STING signaling pathway, promote CD8+ T-cell-dependent anti-tumor immunity, and overcome anti-PD1 refractoriness in vivo. Thus, a key function of casp3/7 is to inhibit inflammation caused by the cytoplasmic release of mtRNA, and pharmacological modulation of this pathway increases the immunogenicity of chemotherapy-induced apoptosis.
  3. Curr Pharm Des. 2023 Mar 13.
      BACKGROUND: Mitochondria are multifunctional organelles, which participate in biochemical processes. Mitochondria acts as primary energy producers and biosynthetic centers of cells, which are involved in oxidative stress responses and cell signaling transduction. Among numerous potential mechanisms of mitochondrial dysfunction, the opening of the mitochondrial permeability transition pore (mPTP) is a major determinant of mitochondrial dysfunction to induce cellular damage or death. A plenty of studies have provided evidence that the abnormal opening of mPTP induces the loss of mitochondrial membrane potential, the impairment calcium homeostasis and the decrease of ATP production. Cyclophilin D (CypD), localized in the mitochondrial transition pore, is a mitochondrial chaperone that has been regarded as a prominent mediator of mPTP.METHODS: This review describes the relationship between CypD, mPTP, and CypD-mPTP inhibitors through systematic investigation of recent relevant literature.
    RESULTS: Here, we have highlighted that inhibiting the activity of CypD protects models of some diseases, including ischaemia/reperfusion injury (IRI), neurodegenerative disorders and so on. Knockdown studies have demonstrated that CypD possibly is mediated by its peptidyl-prolyl cis-trans isomerase activity, while the primary targets of CypD remain obscure. The target of CypD-mPTP inhibitor can alleviate mPTP opening-induced cell death. The present review is focused on the role of CypD as a prominent mediator of the mPTP, further providing insight into the physiological function of mPTP and its regulation by CypD.
    CONCLUSION: Blocking the opening of mPTP by inhibiting CypD might be a new promising approach for suppressing cell death, which will suggest novel therapeutic approaches for mitochondria-related diseases.
    Keywords:  cyclophilin D; mechanisms; mitochondria; mitochondrial permeability transition pore
  4. Eur J Neurosci. 2023 Mar 17.
      The innate immune response plays an important role in the pathological process of ischemic stroke. Increasing evidence suggests that the inflammatory response triggered by the innate immune system hinders neurological and behavioral recovery after stroke. The perception of abnormal DNA and its downstream effects are an essential part of the innate immune system. The abnormal DNA is the major inducing factor for innate immune response and is sensed by a series of DNA sensors. In this review, we discussed the multiple roles of DNA sensing in the pathological process of ischemic stroke, with a special focus on DNA sensors Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2) and cyclic GMP-AMP synthase (cGAS).
    Keywords:  Abnormal DNA; DNA sensors; Inflammatory response; Innate immune response; Ischemic stroke
  5. Reprod Biol Endocrinol. 2023 Mar 17. 21(1): 27
      The decline of oocyte quality has profound impacts on fertilization, implantation, embryonic development, and the genetic quality of future generations. One factor that is often ignored but is involved in the decline of oocyte quality is mitochondrial DNA (mtDNA) abnormalities. Abnormalities in mtDNA affect the energy production of mitochondria, the dynamic balance of the mitochondrial network, and the pathogenesis of mtDNA diseases in offspring. In this review, we have detailed the characteristics of mtDNA in oocytes and the maternal inheritance of mtDNA. Next, we summarized the mtDNA abnormalities in oocytes derived from aging, diabetes, obesity, and assisted reproductive technology (ART) in an attempt to further elucidate the possible mechanisms underlying the decline in oocyte health. Because multiple infertility factors are often involved when an individual is infertile, a comprehensive understanding of the individual effects of each infertility-related factor on mtDNA is necessary. Herein, we consider the influence of infertility-related factors on the mtDNA of the oocyte as a collective perspective for the first time, providing a supplementary angle and reference for multi-directional improvement strategies of oocyte quality in the future. In addition, we highlight the importance of studying ART-derived mitochondrial abnormalities during every ART procedure.
    Keywords:  Aging; Assisted reproductive technology; Diabetes; Mitochondria; Obesity; Reproduction; mtDNA
  6. Stem Cell Res Ther. 2023 Mar 16. 14(1): 40
      BACKGROUND: Mitochondrial dysfunction caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA, which codes for mitochondrial components, are known to be associated with various genetic and congenital disorders. These mitochondrial disorders not only impair energy production but also affect mitochondrial functions and have no effective treatment. Mesenchymal stem cells (MSCs) are known to migrate to damaged sites and carry out mitochondrial transfer. MSCs grown using conventional culture methods exhibit heterogeneous cellular characteristics. In contrast, highly purified MSCs, namely the rapidly expanding clones (RECs) isolated by single-cell sorting, display uniform MSCs functionality. Therefore, we examined the differences between RECs and MSCs to assess the efficacy of mitochondrial transfer.METHODS: We established mitochondria-deficient cell lines (ρ0 A549 and ρ0 HeLa cell lines) using ethidium bromide. Mitochondrial transfer from RECs/MSCs to ρ0 cells was confirmed by PCR and flow cytometry analysis. We examined several mitochondrial functions including ATP, reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate (OCR). The route of mitochondrial transfer was identified using inhibition assays for microtubules/tunneling nanotubes, gap junctions, or microvesicles using transwell assay and molecular inhibitors.
    RESULTS: Co-culture of ρ0 cells with MSCs or RECs led to restoration of the mtDNA content. RECs transferred more mitochondria to ρ0 cells compared to that by MSCs. The recovery of mitochondrial function, including ATP, OCR, mitochondrial membrane potential, and mitochondrial swelling in ρ0 cells co-cultured with RECs was superior than that in cells co-cultured with MSCs. Inhibition assays for each pathway revealed that RECs were sensitive to endocytosis inhibitor, dynasore.
    CONCLUSIONS: RECs might serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction by donating healthy mitochondria.
    Keywords:  Mesenchymal stem cells (MSCs); Mitochondrial dysfunction; Mitochondrial transfer; Rapidly expanding clones (RECs)
  7. Cancer Immunol Res. 2023 Mar 15. pii: CIR-22-0483. [Epub ahead of print]
      Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I interferons (IFNs) and other cytokines. Pharmacological activation of STING is considered a potent therapeutic strategy in cancer. In this study, we employed a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP-STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.
  8. Mol Biol Cell. 2023 Mar 15. mbcE22040119
      The actin cytoskeleton is a ubiquitous participant in cellular functions that maintain viability, but how it controls programmed cell death is not well understood. Here we show that in response to DNA damage, human cells form a juxtanuclear F-actin-rich territory that coordinates the organized progression of apoptosome assembly to caspase activation. This cytoskeletal compartment is created by the actin nucleation factors JMY, WHAMM, and the Arp2/3 complex, and it excludes proteins that inhibit JMY and WHAMM activity. Within the territory, mitochondria undergo outer membrane permeabilization and JMY localization overlaps with punctate structures containing the core apoptosome components cytochrome c and Apaf-1. The F-actin-rich area also encompasses initiator caspase-9 and clusters of a cleaved form of executioner caspase-3 but restricts accessibility of the caspase inhibitor XIAP. The clustering and potency of caspase-3 activation are positively regulated by the amount of actin polymerized by JMY and WHAMM. These results indicate that JMY-mediated actin reorganization functions in apoptotic signaling by coupling the biogenesis of apoptosomes to the localized processing of caspases. [Media: see text].
  9. Res Sq. 2023 Feb 27. pii: [Epub ahead of print]
      Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. Methods: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
  10. Sci Rep. 2023 Mar 14. 13(1): 4193
      Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.
  11. Front Cell Dev Biol. 2023 ;11 1118524
      Age-related macular degeneration (AMD) is a neurodegenerative disease and a leading cause of irreversible vision loss in the developed world. While not classically described as an inflammatory disease, a growing body of evidence has implicated several components of the innate immune system in the pathophysiology of age-related macular degeneration. In particular, complement activation, microglial involvement, and blood-retinal-barrier disruption have been shown to play key roles in disease progression, and subsequent vision loss. This review discusses the role of the innate immune system in age-related macular degeneration as well as recent developments in single-cell transcriptomics that help advance the understanding and treatment of age-related macular degeneration. We also explore the several potential therapeutic targets for age-related macular degeneration in the context of innate immune activation.
    Keywords:  age-related macular degeneration (AMD); innate immunity; neurodegeneration; neuroimmune biology; neuroinflammation