bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–12–17
eleven papers selected by
Marco Tigano, Thomas Jefferson University
  1. The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
  2. Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
  3. Mitochondrial temperature homeostasis resists external metabolic stresses.
  4. The critical roles of STING in mitochondrial homeostasis.
  5. "ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane".
  6. Activation of mitochondrial DNA-mediated cGAS-STING pathway contributes to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord.
  7. Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.
  8. Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.
  9. Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response.
  10. The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
  11. Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression.
  1. Mol Neurobiol. 2023 Dec 12.
    The Protective Mechanism of TFAM on Mitochondrial DNA and its Role in Neurodegenerative Diseases.
    Ying Song, Wenjun Wang, Beibei Wang, Qiwen Shi.
      Mitochondrial transcription factor A (TFAM) is a mitochondrial protein encoded by nuclear genes and transported from the cytoplasm to the mitochondria. TFAM is essential for the maintenance, expression, and delivery of mitochondrial DNA (mtDNA) and can regulate the replication and transcription of mtDNA. TFAM is associated with the formation of mtDNA nucleomimetic structures, mtDNA repair, and mtDNA stability. However, the mechanism by which TFAM protects mtDNA is still being studied. This review provides a summary of the protective mechanism of TFAM on mtDNA including the discrete regulatory effects of TFAM acetylation and phosphorylation on mtDNA, the regulation of Ca2+ levels by TFAM to activate transcription in mitochondria, and the increased binding of TFAM to mtDNA damage hot spots. This review also discusses the association between TFAM and some neurodegenerative diseases.
    Keywords:  Mitochondria; Mitochondrial DNA; Mitochondrial transcription factor A; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-023-03841-7
  2. bioRxiv. 2023 Dec 01. pii: 2023.11.30.569464. [Epub ahead of print]
    Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
    John Sturgis, Rupesh Singh, Quinn Caron, Ivy S Samuels, Thomas Micheal Shiju, Aditi Mukkara, Paul Freedman, Vera L Bonilha.
      Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a Polymerase gamma (POLG) deficiency model, the POLG D257A mutator mice (PolgD257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the POLG D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mitochondria morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress observed in the retina or RPE of POLGD257A mice. Additionally, POLGD257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mitochondrial markers displayed decreased abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mitochondrial DNA mutations leads to impaired mitochondrial function and accelerated aging, resulting in retinal degeneration.
    DOI:  https://doi.org/10.1101/2023.11.30.569464
  3. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  4. Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938
    The critical roles of STING in mitochondrial homeostasis.
    Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
    Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING
    DOI:  https://doi.org/10.1016/j.bcp.2023.115938
  5. Free Radic Biol Med. 2023 Dec 11. pii: S0891-5849(23)01151-6. [Epub ahead of print]
    "ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane".
    Paula Gaudó, Elena de Tomás-Mateo, Nuria Garrido-Pérez, Alfredo Santana, Eduardo Ruiz-Pesini, Julio Montoya, Pilar Bayona-Bafaluy.
      Mitochondrial ATAD3A is an ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme, involved in the structural organization of the inner mitochondrial membrane and of increasing importance in childhood disease. In humans, two ATAD3A paralogs arose by gene duplication during evolution: ATAD3B and ATAD3C. Here we investigate the cellular activities of the ATAD3C paralog that has been considered a pseudogene. We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. Overexpression of ATAD3C, but not of ATAD3A, in fibroblasts caused a decrease in cell proliferation and oxygen consumption rate, and an increase of cellular ROS. This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell.
    Keywords:  ATAD3A; ATAD3B; ATAD3C; Mitochondria; OXPHOS; Respiratory complexes; Respiratory supercomplexes
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.006
  6. Int Immunopharmacol. 2023 Dec 11. pii: S1567-5769(23)01675-2. [Epub ahead of print]127 111348
    Activation of mitochondrial DNA-mediated cGAS-STING pathway contributes to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord.
    Yuye Chen, Yingjie Hu, Xiao He, Hu Zang, Rao Sun, Chang Zhu, Wenlong Yao.
      Chronic postsurgical pain (CPSP) is increasingly recognized as a public health issue. Recent studies indicated the innate immune pathway of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) was involved in pain regulation. However, the detailed mechanisms remain unclear. Previous studies found A1 reactive astrocytes in the spinal cord contributed to CPSP. This study aimed to investigate the roles and mechanisms of the cGAS-STING pathway in regulating the generation of A1 reactive astrocytes during CPSP. First, CPSP model was established using skin/muscle incision and retraction (SMIR) in rats. We found that cGAS-STING pathway was activated accompanied with an increase in mitochondrial DNA in the cytosol in the spinal cord following SMIR. Second, a STING inhibitor C-176 was intrathecally administrated. We found that C-176 decreased the expression of type I interferons and A1 reactive astrocytes in the spinal cord, and alleviated mechanical allodynia in SMIR rats. Third, cyclosporin A as a mitochondrial permeability transition pore blocker was intrathecally administrated. We found that cyclosporin A decreased the leakage of mitochondrial DNA and inhibited the activation of cGAS-STING pathway. Compared with C-176, cyclosporin A exhibits similar analgesic effects. The expression of type I interferons and A1 reactive astrocytes in the spinal cord were also down-regulated after intervention with cyclosporin A. Moreover, simultaneous administration of cyclosporin A and C-176 did not show synergistic effects in SMIR rats. Therefore, our study demonstrated that the cGAS-STING pathway activated by the leakage of mitochondrial DNA contributed to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord.
    Keywords:  A1 reactive astrocytes; Chronic postsurgical pain; Cyclic guanosine monophosphate-adenosine monophosphate synthase; Interferon; Mitochondrial permeability transition pore; Stimulator of interferon gene
    DOI:  https://doi.org/10.1016/j.intimp.2023.111348
  7. bioRxiv. 2023 Nov 28. pii: 2023.11.27.568924. [Epub ahead of print]
    Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.
    Amit Prabhakar, Rahul Kumar, Meetu Wadhwa, Prajakta Ghatpande, Jingkun Zhang, Ziwen Zhao, Carlos O Lizama, Bhushan N Kharbikar, Stefan Gräf, Carmen M Treacy, Nicholas W Morrell, Brian B Graham, Giorgio Lagna, Akiko Hata.
      Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, elevation of vascular permeability, and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygous BMPR2 mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD.
    DOI:  https://doi.org/10.1101/2023.11.27.568924
  8. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 12.
    Molecular Mechanisms Underlying TNFα Induced Mitochondrial Fragmentation in Human Airway Smooth Muscle Cells.
    Debanjali Dasgupta, Sanjana Mahadev Bhat, Claire Creighton, Catherin Cortes, Philippe F Delmotte, Gary C Sieck.
      Tumor necrosis factor α (TNFa), a proinflammatory cytokine, plays a significant role in mediating the effects of acute inflammation in response to allergens, pollutants, and respiratory infections. Previously, we showed that acute exposure to TNFa induces mitochondrial fragmentation in human airway smooth muscle (hASM) cells, which is associated with increased expression of dynamin-related protein 1 (DRP1). Phosphorylation of DRP1 at serine 616 (pDRP1S616) promotes its translocation and binding to the outer mitochondrial membrane (OMM) and mediates mitochondrial fragmentation. Previously, we reported that TNFa exposure triggers protein unfolding and triggers an endoplasmic reticulum (ER) stress response involving phosphorylation of inositol-requiring enzyme 1α (pIRE1a) at serine 724 (pIRE1aS724) and subsequent splicing of X-box binding protein 1 (XBP1s) in hASM cells. We hypothesize that TNFa-mediated activation of the pIRE1aS724/XBP1s ER stress pathway in hASM cells transcriptionally activates genes that encode kinases responsible for pDRP1S616 phosphorylation. Using 3-D confocal imaging of MitoTracker green-labeled mitochondria, we found that TNFa treatment for 6 h induces mitochondrial fragmentation in hASM cells. We also confirmed that 6 h TNFa treatment activates the pIRE1a/XBP1s ER stress pathway. Using in silico analysis and ChIP assay, we showed that CDK1 and CDK5, kinases involved in the phosphorylation of pDRP1S616, are transcriptionally targeted by XBP1s. TNFa treatment increased the binding affinity of XBP1s on the promoter regions of CDK1 and CDK5, and this was associated with an increase in pDRP1S616 and mitochondria fragmentation. This study reveals a new underlying molecular mechanism for TNFa-induced mitochondrial fragmentation in hASM cells.
    Keywords:  Airway smooth muscle; DRP1 phosphorylation; ER stress; airway inflammation; mitochondrial fragmentation
    DOI:  https://doi.org/10.1152/ajplung.00198.2023
  9. Sci Signal. 2023 Dec 12. 16(815): eabq1173
    Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response.
    Zbigniew Korwek, Maciej Czerkies, Joanna Jaruszewicz-Błońska, Wiktor Prus, Ilona Kosiuk, Marek Kochańczyk, Tomasz Lipniacki.
      Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting IFNB transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3-NF-κB and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-κB induced, which converts IFN-β-responding cells to IFN-β-secreting cells.
    DOI:  https://doi.org/10.1126/scisignal.abq1173
  10. Biochim Biophys Acta Mol Cell Res. 2023 Dec 11. pii: S0167-4889(23)00221-5. [Epub ahead of print] 119648
    The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
    Xiao-Long Su, Zhi-Ren Su, Wei-Hua Xu.
      Diapause is a widespread adaptation of insects that enables them to survive during unfavorable seasons and is characterized by suppressed metabolism and increased lifespan. Previous works have demonstrated that high levels of reactive oxygen species (ROS) and hypoxia-inducible factor-1α (HIF-1α) in the pupal brain of the moth Helicoverpa armigera induce diapause and extend lifespan by downregulating mitochondrial transcription factor A (TFAM). However, the molecular mechanisms of ROS-HIF-1α regulating metabolic activity to extend lifespan are still poorly understood. Here, we show that the mitochondrial abundance in diapause-type pupal brains is markedly lower than that in their nondiapause-type pupae, suggesting that ROS-HIF-1α signaling negatively regulates the number of mitochondria. The protease Lon, a major mitochondrial matrix protease, can respond to ROS signals. It is activated by transcription factor HIF-1α, which specifically binds the LON promoter to promote its expression. A high level of LON mediates the degradation of TFAM, which is a crucial factor in regulating mitochondrial abundance and metabolic activity. We believe this is the first report that a previously unrecognized regulatory pathway, ROS-HIF-1α-LON-TFAM, reduces mitochondrial activity to induce diapause, extending insect lifespan.
    Keywords:  Diapause; HIF-1α; LON; ROS; TFAM
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119648
  11. Cancer Cell Int. 2023 Dec 08. 23(1): 315
    Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression.
    Felix Hiebinger, Aiste Kudulyte, Huanting Chi, Sebastian Burbano De Lara, Doroteja Ilic, Barbara Helm, Hendrik Welsch, Viet Loan Dao Thi, Ursula Klingmüller, Marco Binder.
      Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.
    Keywords:  Cancer; Cell proliferation; Hepatocellular carcinoma; Immunoediting; Interferon; Interferon resistance; Signalling
    DOI:  https://doi.org/10.1186/s12935-023-03150-y
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