bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒04‒09
seven papers selected by
Marco Tigano
Thomas Jefferson University
  1. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
  2. Ends end it via mitochondria: A telomere-dependent tumor suppressive mechanism acts during replicative crisis.
  3. Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis.
  4. Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.
  5. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  6. Effective differentiation of double negative thymocytes requires high fidelity replication of mitochondrial DNA in an age dependent manner.
  7. An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
  1. Free Radic Biol Med. 2023 Apr 01. pii: S0891-5849(23)00368-4. [Epub ahead of print]
    Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
    Mansoor Hussain, Xixia Chu, Burcin Duan Sahbaz, Samuel Gray, Komal Pekhale, Jae-Hyeon Park, Deborah L Croteau, Vilhelm A Bohr.
      Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.262
  2. Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00200-9. [Epub ahead of print]83(7): 1027-1029
    Ends end it via mitochondria: A telomere-dependent tumor suppressive mechanism acts during replicative crisis.
    Venus Marie Gaela, Liuh-Yow Chen.
      Nassour et al.1 report that telomere dysfunction communicates with mitochondria via the ZBP1-TERRA-MAVS axis. This pathway activates a detrimental innate immune response that may promote the elimination of cells prone to oncogenic transformation during replicative crisis, thus serving as a telomere-dependent tumor-suppressive mechanism.
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.012
  3. Sci Rep. 2023 Apr 06. 13(1): 5635
    Immunomodulatory therapy with glatiramer acetate reduces endoplasmic reticulum stress and mitochondrial dysfunction in experimental autoimmune encephalomyelitis.
    Tapas K Makar, Poornachander R Guda, Sugata Ray, Sanketh Andhavarapu, Kaspar Keledjian, Volodymyr Gerzanich, J Marc Simard, Vamshi K C Nimmagadda, Christopher T Bever.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are found in lesions of multiple sclerosis (MS) and animal models of MS such as experimental autoimmune encephalomyelitis (EAE), and may contribute to the neuronal loss that underlies permanent impairment. We investigated whether glatiramer acetate (GA) can reduce these changes in the spinal cords of chronic EAE mice by using routine histology, immunostaining, and electron microscopy. EAE spinal cord tissue exhibited increased inflammation, demyelination, mitochondrial dysfunction, ER stress, downregulation of NAD+ dependent pathways, and increased neuronal death. GA reversed these pathological changes, suggesting that immunomodulating therapy can indirectly induce neuroprotective effects in the CNS by mediating ER stress.
    DOI:  https://doi.org/10.1038/s41598-023-29852-x
  4. Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00167-3. [Epub ahead of print]83(7): 1180-1196.e8
    Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.
    Max Paget, Cristhian Cadena, Sadeem Ahmad, Hai-Tao Wang, Tristan X Jordan, Ehyun Kim, Beechui Koo, Shawn M Lyons, Pavel Ivanov, Benjamin tenOever, Xin Mu, Sun Hur.
      Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here, we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in the controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independently of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis by dampening both toxic immune response and viral replication.
    Keywords:  ADAR1; RIG-I-like receptor; antiviral signaling; dsRNA; immune-mediated apoptosis; immunopathology; innate immunity; integrated stress response; molecular condensate; stress granule
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.010
  5. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  6. Front Immunol. 2023 ;14 1128626
    Effective differentiation of double negative thymocytes requires high fidelity replication of mitochondrial DNA in an age dependent manner.
    Candice B Limper, Narda Bondah, Daphne Zhu, Alanis N Villanueva, Uchenna K Chukwukere, Weishan Huang, Avery August.
      One of the most proliferative periods for T cells occurs during their development in the thymus. Increased DNA replication can result in increased DNA mutations in the nuclear genome, but also in mitochondrial genomes. A high frequency of mitochondrial DNA mutations can lead to abnormal mitochondrial function and have negative implications on human health. Furthermore, aging is accompanied by an increase in such mutations through oxidative damage and replication errors. Increased mitochondrial DNA mutations cause loss of mitochondrial protein function, and decrease energy production, substrates, and metabolites. Here we have evaluated the effect of increased mitochondrial DNA mutations on T cell development in the thymus. Using mice carrying a mutant mitochondrial DNA polymerase γ (PolG) that causes increased mitochondrial DNA mutations, we show that high fidelity replication of mitochondrial DNA is pivotal for proper T cell development. Reducing the fidelity of mitochondrial DNA replication results in a premature age-dependent reduction in the total number of CD4/CD8 double negative and double positive thymocytes. Analysis of mitochondrial density in thymocyte subpopulations suggests that this may be due to reduced proliferation in specific double negative stages. Taken together, this work suggests that T cell development is regulated by the ability of mitochondria to faithfully replicate their DNA.
    Keywords:  DNA polymerase γ; T cell development; aging; mitochondria; mutator mice; proliferation; thymus
    DOI:  https://doi.org/10.3389/fimmu.2023.1128626
  7. Life Sci Alliance. 2023 Jun;pii: e202201767. [Epub ahead of print]6(6):
    An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
    Richard Miallot, Virginie Millet, Yann Groult, Angelika Modelska, Lydie Crescence, Sandrine Roulland, Sandrine Henri, Bernard Malissen, Nicolas Brouilly, Laurence Panicot-Dubois, Renaud Vincentelli, Gerlind Sulzenbacher, Pascal Finetti, Aurélie Dutour, Jean-Yves Blay, François Bertucci, Franck Galland, Philippe Naquet.
      Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.
    DOI:  https://doi.org/10.26508/lsa.202201767
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