bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022‒12‒04
24 papers selected by
Marco Tigano
Thomas Jefferson University
  1. Mitochondria and cell death-associated inflammation.
  2. Necroptosis-dependent immunogenicity of cisplatin: implications for enhancing the radiation-induced abscopal effect.
  3. Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.
  4. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.
  5. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
  6. Horizontal transfer of tRNA genes to mitochondrial plasmids facilitates gene loss from fungal mitochondrial DNA.
  7. Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells.
  8. Mathematical modeling and analysis of mitochondrial retrograde signaling dynamics.
  9. The mitochondrial gene-CMPK2 functions as a rheostat for macrophage homeostasis.
  10. STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.
  11. Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
  12. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
  13. The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways.
  14. Mitochondria-associated niches in health and disease.
  15. An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
  16. AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.
  17. p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol.
  18. Mitochondrial RNA stimulates beige adipocyte development in young mice.
  19. Mitochondrial respiration and dynamics of in vivo neural stem cells.
  20. Mitochondria: how eminent in ageing and neurodegenerative disorders?
  21. The human signal peptidase complex acts as a quality control enzyme for membrane proteins.
  22. TDP-43 knockdown in mouse model of ALS leads to dsRNA deposition, gliosis, and neurodegeneration in the spinal cord.
  23. Generation of a homozygous FIS1 knockout human embryonic stem cell line GIBHe015-B by CRISPR/Cas9 system.
  24. PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment.
  1. Cell Death Differ. 2022 Nov 29.
    Mitochondria and cell death-associated inflammation.
    Esmee Vringer, Stephen W G Tait.
      Mitochondria have recently emerged as key drivers of inflammation associated with cell death. Many of the pro-inflammatory pathways activated during cell death occur upon mitochondrial outer membrane permeabilization (MOMP), the pivotal commitment point to cell death during mitochondrial apoptosis. Permeabilised mitochondria trigger inflammation, in part, through the release of mitochondrial-derived damage-associated molecular patterns (DAMPs). Caspases, while dispensable for cell death during mitochondrial apoptosis, inhibit activation of pro-inflammatory pathways after MOMP. Some of these mitochondrial-activated inflammatory pathways can be traced back to the bacterial ancestry of mitochondria. For instance, mtDNA and bacterial DNA are highly similar thereby activating similar cell autonomous immune signalling pathways. The bacterial origin of mitochondria suggests that inflammatory pathways found in cytosol-invading bacteria may be relevant to mitochondrial-driven inflammation after MOMP. In this review, we discuss how mitochondria can initiate inflammation during cell death highlighting parallels with bacterial activation of inflammation. Moreover, we discuss the roles of mitochondrial inflammation during cell death and how these processes may potentially be harnessed therapeutically, for instance to improve cancer treatment.
    DOI:  https://doi.org/10.1038/s41418-022-01094-w
  2. Clin Cancer Res. 2022 Nov 30. pii: CCR-22-1591. [Epub ahead of print]
    Necroptosis-dependent immunogenicity of cisplatin: implications for enhancing the radiation-induced abscopal effect.
    Ren Luo, Kateryna Onyshchenko, Liqun Wang, Simone Gaedicke, Anca-Ligia Grosu, Elke Firat, Gabriele Niedermann.
      PURPOSE: Cisplatin is increasingly used in chemoimmunotherapy and may enhance the T cell-dependent radiation-induced abscopal effect, but how it promotes antitumor immunity is poorly understood. We investigated whether and why cisplatin is immunogenic, and the implications for the cisplatin-enhanced abscopal effect.EXPERIMENTAL DESIGN: Cisplatin, carboplatin, and the well-known immunogenic cell death (ICD) inducer oxaliplatin were compared for their potency to enhance the abscopal effect and induce IFN-I and extracellular ATP, danger signals of ICD. The hypothetical role of necroptosis and associated DAMPs for cisplatin-induced ICD was investigated by inhibitors and knockout cells in vitro and in two tumor models in mice. A novel necroptosis signature for tumor immune cell infiltration and therapy response was developed.
    RESULTS: Cisplatin enhanced the abscopal effect more strongly than oxaliplatin or carboplatin. This correlated with higher induction of IFN-I and extracellular ATP by cisplatin, in a necroptosis-dependent manner. Cisplatin triggered RIPK3-dependent tumor cell necroptosis causing cytosolic mitochondrial DNA (mtDNA) release, initiating the cGAS-STING pathway and IFN-I secretion promoting T cell cross-priming by dendritic cells (DCs). Accordingly, tumor cell RIPK3 or mtDNA deficiency and loss of IFN-I or ATP signaling diminished the cisplatin-enhanced abscopal effect. Cisplatin-treated tumor cells were immunogenic in vaccination experiments, depending on RIPK3 and mtDNA. In human tumor transcriptome analysis, necroptotic features correlated with abundant CD8+ T cells/DCs, sparse immunosuppressive cells, and immunotherapy response.
    CONCLUSIONS: Cisplatin induces antitumor immunity through necroptosis-mediated ICD. Our findings may help explain the benefits of cisplatin in chemo(radio)immunotherapies and develop clinical trials to investigate whether cisplatin enhances the abscopal effect in patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1591
  3. Neurobiol Aging. 2022 Nov 06. pii: S0197-4580(22)00231-7. [Epub ahead of print]121 157-165
    Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.
    Sung-Eun Noh, Seok Jae Lee, Tae Geol Lee, Kyu-Sang Park, Jeong Hun Kim.
      Retinal pigment epithelium (RPE) damage is a major factor in age-related macular degeneration (AMD). The RPE in AMD shows mitochondrial dysfunction suggesting an association of AMD with mitochondrial function. Therefore, exogenous mitochondrial transplantation for restoring and replacing dysfunctional mitochondria may be an effective therapeutic strategy for AMD. Here, we investigated the effects of extrinsic mitochondrial transplantation on senescence-induced ARPE-19 cells. We demonstrated mitochondrial dysfunction in replicative senescence-induced ARPE-19 cells after repeated passage. Imbalanced mitophagy and mitochondrial dynamics resulted in increased mitochondrial numbers and elevated levels of mitochondrial and intracellular reactive oxygen species. Exogenous mitochondrial transplantation improved mitochondrial dysfunction and alleviated cellular senescence hallmarks, such as increased cell size, increased senescence-associated β-galactosidase activity, augmented NF-κB activity, increased inflammatory cytokines, and upregulated the cyclin-dependent kinase inhibitors p21 and p16. Further, cellular senescence properties were improved by exogenous mitochondrial transplantation in oxidative stress-induced senescent ARPE-19 cells. These results indicate that exogenous mitochondrial transplantation modulates cellular senescence and may be considered a novel therapeutic strategy for AMD.
    Keywords:  Age-related macular degeneration; Exogenous mitochondrial transplantation; Oxidative stress; Retinal pigment epithelium; Senescence
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.003
  4. Nat Commun. 2022 Dec 01. 13(1): 7400
    PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.
    Zdenek Andrysik, Kelly D Sullivan, Jeffrey S Kieft, Joaquin M Espinosa.
      The p53 transcription factor is a master regulator of cellular stress responses inhibited by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces apoptosis in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2α, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2α phosphorylation. Pharmacological induction of eIF2α phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2α-ATF4, with clear therapeutic implications.
    DOI:  https://doi.org/10.1038/s41467-022-35089-5
  5. Nat Commun. 2022 Nov 28. 13(1): 7338
    Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
    Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.
      Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
    DOI:  https://doi.org/10.1038/s41467-022-34632-8
  6. Curr Genet. 2022 Nov 30.
    Horizontal transfer of tRNA genes to mitochondrial plasmids facilitates gene loss from fungal mitochondrial DNA.
    Mathijs Nieuwenhuis, Jeroen Groeneveld, Duur K Aanen.
      Fungal and plant mitochondria are known to exchange DNA with retroviral plasmids. Transfer of plasmid DNA to the organellar genome is best known and occurs through wholesale insertion of the plasmid. Less well known is the transfer of organellar DNA to plasmids, in particular tRNA genes. Presently, it is unknown whether fungal plasmids can adopt mitochondrial functions such as tRNA production through horizontal gene transfer. In this paper, we studied the exchange of DNA between fungal linear plasmids and fungal mtDNA, mainly focusing on the basidiomycete family Lyophyllaceae. We report at least six independent transfers of complete tRNA genes to fungal plasmids. Furthermore, we discovered two independent cases of loss of a tRNA gene from a fungal mitochondrial genome following transfer of such a gene to a linear mitochondrial plasmid. We propose that loss of a tRNA gene from mtDNA following its transfer to a plasmid creates a mutualistic dependency of the host mtDNA on the plasmid. We also find that tRNA genes transferred to plasmids encode codons that occur at the lowest frequency in the host mitochondrial genomes, possibly due to a higher number of unused transcripts. We discuss the potential consequences of mtDNA transfer to plasmids for both the host mtDNA and the plasmid.
    Keywords:  Fungi; Horizontal gene transfer; Lyophyllaceae; Mitochondrial plasmids; Phylogenetics; mtDNA
    DOI:  https://doi.org/10.1007/s00294-022-01259-7
  7. BMC Cancer. 2022 Dec 02. 22(1): 1254
    Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells.
    Wioleta Dudka, Grazyna Hoser, Shamba S Mondal, Laura Turos-Korgul, Julian Swatler, Monika Kusio-Kobialka, Magdalena Wołczyk, Agata Klejman, Marta Brewinska-Olchowik, Agata Kominek, Milena Wiech, Marcin M Machnicki, Ilona Seferynska, Tomasz Stoklosa, Katarzyna Piwocka.
      The integrated stress response (ISR) facilitates cellular adaptation to unfavorable conditions by reprogramming the cellular response. ISR activation was reported in neurological disorders and solid tumors; however, the function of ISR and its role as a possible therapeutic target in hematological malignancies still remain largely unexplored. Previously, we showed that the ISR is activated in chronic myeloid leukemia (CML) cells and correlates with blastic transformation and tyrosine kinase inhibitor (TKI) resistance. Moreover, the ISR was additionally activated in response to imatinib as a type of protective internal signaling. Here, we show that ISR inhibition combined with imatinib treatment sensitized and more effectively eradicated leukemic cells both in vitro and in vivo compared to treatment with single agents. The combined treatment specifically inhibited the STAT5 and RAS/RAF/MEK/ERK pathways, which are recognized as drivers of resistance. Mechanistically, this drug combination attenuated both interacting signaling networks, leading to BCR-ABL1- and ISR-dependent STAT5 activation. Consequently, leukemia engraftment in patient-derived xenograft mice bearing CD34+ TKI-resistant CML blasts carrying PTPN11 mutation responsible for hyperactivation of the RAS/RAF/MAPK and JAK/STAT5 pathways was decreased upon double treatment. This correlated with the downregulation of genes related to the RAS/RAF/MAPK, JAK/STAT5 and stress response pathways and was associated with lower expression of STAT5-target genes regulating proliferation, viability and the stress response. Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment.
    Keywords:  CML; ISR; ISRIB; Myeloid leukemia; PTPN11; RAS/RAF/MAPK; STAT5; TKI resistance
    DOI:  https://doi.org/10.1186/s12885-022-10289-w
  8. iScience. 2022 Dec 22. 25(12): 105502
    Mathematical modeling and analysis of mitochondrial retrograde signaling dynamics.
    Shao-Ting Chiu, Wen-Wei Tseng, An-Chi Wei.
      Mitochondria, semi-autonomous eukaryotic organelles, participate in energy production and metabolism, making mitochondrial quality control crucial. As most mitochondrial proteins are encoded by nuclear genes, maintaining mitochondrial function and quality depends on proper mitochondria-nucleus communication and designated mitochondrial retrograde signaling. Early studies focused on retrograde signaling participants and specific gene knockouts. However, mitochondrial signal modulation remains elusive. A mathematical model based on ordinary differential equations was proposed to simulate signal propagation to nucleus following mitochondrial damage in yeast. Mitochondrial retrograde signaling decisions were described using a Boolean model. Dynamics of retrograde signaling were analyzed and extended to evaluate the model response to noisy damage signals. Simulation revealed localized protein concentration dynamics, including waveforms, frequency response, and robustness under noise. Retrograde signaling is bistable with localized steady states, and increased damage compromises robustness. We elucidated mitochondrial retrograde signaling, thus providing a basis for drug design against yeast and fungi.
    Keywords:  Biological sciences; Cell biology; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105502
  9. Front Immunol. 2022 ;13 935710
    The mitochondrial gene-CMPK2 functions as a rheostat for macrophage homeostasis.
    Prabhakar Arumugam, Meghna Chauhan, Thejaswitha Rajeev, Rahul Chakraborty, Kanika Bisht, Mahima Madan, Deepthi Shankaran, Sivaprakash Ramalingam, Sheetal Gandotra, Vivek Rao.
      In addition to their role in cellular energy production, mitochondria are increasingly recognized as regulators of the innate immune response of phagocytes. Here, we demonstrate that altering expression levels of the mitochondria-associated enzyme, cytidine monophosphate kinase 2 (CMPK2), disrupts mitochondrial physiology and significantly deregulates the resting immune homeostasis of macrophages. Both CMPK2 silenced and constitutively overexpressing macrophage lines portray mitochondrial stress with marked depolarization of their membrane potential, enhanced reactive oxygen species (ROS), and disturbed architecture culminating in the enhanced expression of the pro-inflammatory genes IL1β, TNFα, and IL8. Interestingly, the long-term modulation of CMPK2 expression resulted in an increased glycolytic flux of macrophages akin to the altered physiological state of activated M1 macrophages. While infection-induced inflammation for restricting pathogens is regulated, our observation of a total dysregulation of basal inflammation by bidirectional alteration of CMPK2 expression only highlights the critical role of this gene in mitochondria-mediated control of inflammation.
    Keywords:  CMPK2; M1 macrophage; immuno-metabolism; infection; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2022.935710
  10. Adv Sci (Weinh). 2022 Nov 29. e2203718
    STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.
    Zhichuan Zhu, Xin Zhou, Hongwei Du, Erica W Cloer, Jiaming Zhang, Liu Mei, Ying Wang, Xianming Tan, Austin J Hepperla, Jeremy M Simon, Jeanette Gowen Cook, Michael B Major, Gianpietro Dotti, Pengda Liu.
      STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.
    Keywords:  2-BP; STING; VDAC2; innate immunity-independent; mTORC1; mitochondrial homeostasis
    DOI:  https://doi.org/10.1002/advs.202203718
  11. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2122073119
    Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.
    Ferdinando Insalata, Hanne Hoitzing, Juvid Aryaman, Nick S Jones.
      The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena.
    Keywords:  aging; biomathematics; evolution; mitochondria; stochastic
    DOI:  https://doi.org/10.1073/pnas.2122073119
  12. Nat Commun. 2022 Dec 02. 13(1): 7414
    Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
    Wei Li, Qi Long, Hao Wu, Yanshuang Zhou, Lifan Duan, Hao Yuan, Yingzhe Ding, Yile Huang, Yi Wu, Jinyu Huang, Delong Liu, Baodan Chen, Jian Zhang, Juntao Qi, Shiwei Du, Linpeng Li, Yang Liu, Zifeng Ruan, Zihuang Liu, Zichao Liu, Yifan Zhao, Jianghuan Lu, Junwei Wang, Wai-Yee Chan, Xingguo Liu.
      Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
    DOI:  https://doi.org/10.1038/s41467-022-35199-0
  13. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2215966119
    The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways.
    Kai Mao, Peter Breen, Gary Ruvkun.
      Surveillance of Caenorhabditis elegans mitochondrial status is coupled to defense responses such as drug detoxification, immunity, antiviral RNA interference (RNAi), and regulation of life span. A cytochrome p540 detoxification gene, cyp-14A4, is specifically activated by mitochondrial dysfunction. The nuclear hormone receptor NHR-45 and the transcriptional Mediator component MDT-15/MED15 are required for the transcriptional activation of cyp-14A4 by mitochondrial mutations, gene inactivations, or toxins. A genetic screen for mutations that fail to activate this cytochrome p450 gene upon drug or mutation-induced mitochondrial dysfunction identified a DNA helicase ARIP-4 that functions in concert with the NHR-45 transcriptional regulatory cascade. In response to mitochondrial dysfunction, ARIP-4 and NHR-45 protein interaction is enhanced, and they relocalize from the nuclear periphery to the interior of intestinal nuclei. NHR-45/ARIP-4 also regulates the transcriptional activation of the eol-1 gene that encodes a decapping enzyme required for enhanced RNAi and transgene silencing of mitochondrial mutants. In the absence of arip-4, animals were more susceptible to the mitochondrial inhibitor antimycin. Thus, ARIP-4 serves as a transcriptional coactivator of NHR-45 to promote this defense response. A null mutation in arip-4 extends the life span and health span of both wild type and a mitochondrial mutant, suggesting that the activation of detoxification pathways is deleterious to health when the mitochondrial dysfunction is caused by mutation that cannot be cytochrome p450-detoxified. Thus, arip-4 acts in a pathway that couples mitochondrial surveillance to the activation of downstream immunity, detoxification, and RNAi responses.
    Keywords:  RNAi; detoxification; healthspan; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2215966119
  14. J Cell Sci. 2022 Dec 01. pii: jcs259634. [Epub ahead of print]135(23):
    Mitochondria-associated niches in health and disease.
    Mateus Milani, Philippe Pihán, Claudio Hetz.
      The appreciation of the importance of interorganelle contacts has steadily increased over the past decades. Advances in imaging, molecular biology and bioinformatic techniques allowed the discovery of new mechanisms involved in the interaction and communication between organelles, providing novel insights into the inner works of a cell. In this Review, with the mitochondria under the spotlight, we discuss the most recent findings on the mechanisms mediating the communication between organelles, focusing on Ca2+ signaling, lipid exchange, cell death and stress responses. Notably, we introduce a new integrative perspective to signaling networks that is regulated by interorganelle interactions - the mitochondria-associated niches - focusing on the link between the molecular determinants of contact sites and their functional outputs, rather than simply physical and structural communication. In addition, we highlight the neuropathological and metabolic implications of alterations in mitochondria-associated niches and outline how this concept might improve our understanding of multi-organelle interactions.
    Keywords:  Apoptosis; Bioenergetics; MAMs; Mitochondria; Mitochondria-associated membranes; Stress responses
    DOI:  https://doi.org/10.1242/jcs.259634
  15. Elife. 2022 Nov 30. pii: e84279. [Epub ahead of print]11
    An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
    Tricia T Nguyen, Gia K Voeltz.
      Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, ABHD16A, as a major regulator of node formation. In the absence of ABHD16A, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes and fission and fusion rates are significantly reduced. ABHD16A contains an acyltransferase motif and an α/β hydrolase domain and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby ABHD16A functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.84279
  16. Int Immunopharmacol. 2022 Dec;pii: S1567-5769(22)00897-9. [Epub ahead of print]113(Pt A): 109413
    AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.
    Yuanyuan Zhou, Ming Li, Zhenglei Wang, Xinguang Lin, Yuanyuan Xu, Shiyuan Feng, Jinfeng Miao.
      Excessive production of reactive oxygen species (ROS) leads to oxidative stress in host cells and affects the progress of disease. Mitochondria are an important source of ROS and their dysfunction is closely related to ROS production. S. uberis is a common causative agent of mastitis. The expression of key enzymes of the mitochondrial apoptotic pathway is increased in mammary epithelial cells after S. uberis stimulation, while expression of proteins related to mitochondrial function is decreased. Drp1, a key protein associated with mitochondrial function, is activated upon infection. Accompanied by mitochondria-cytosol translocation of Drp1, Fis1 expression is significantly upregulated while Mfn1 expression is downregulated implying that the balance of mitochondrial dynamics is disrupted. This leads to mitochondrial fragmentation, decreased mitochondrial membrane potential, higher levels of mROS and oxidative injury. The AMPK activator AICAR inhibits the increased phosphorylation of Drp1 and the translocation of Drp1 to mitochondria by salvaging mitochondrial function in an AMPK/Drp1 dependent manner, which has a similar effect to Drp1 inhibitor Mdivi-1. These data show that AMPK, as an upstream negative regulator of Drp1, ameliorates mitochondrial dysfunction induced by S. uberis infection.
    Keywords:  AMPK; Drp1; Mitochondria; Streptococcus uberis
    DOI:  https://doi.org/10.1016/j.intimp.2022.109413
  17. Cell Death Dis. 2022 Nov 29. 13(11): 1009
    p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol.
    Max J Carlsson, Anastasia S Vollmer, Philipp Demuth, Daniel Heylmann, Diana Reich, Caroline Quarz, Birgit Rasenberger, Teodora Nikolova, Thomas G Hofmann, Markus Christmann, Julia A Fuhlbrueck, Simone Stegmüller, Elke Richling, Alexander T Cartus, Jörg Fahrer.
      Liver cancer is one of the most frequent tumor entities worldwide, which is causally linked to viral infection, fatty liver disease, life-style factors and food-borne carcinogens, particularly aflatoxins. Moreover, genotoxic plant toxins including phenylpropenes are suspected human liver carcinogens. The phenylpropene methyleugenol (ME) is a constituent of essential oils in many plants and occurs in herbal medicines, food, and cosmetics. Following its uptake, ME undergoes Cytochrome P450 (CYP) and sulfotransferase 1A1 (SULT1A1)-dependent metabolic activation, giving rise to DNA damage. However, little is known about the cellular response to the induced DNA adducts. Here, we made use of different SULT1A1-proficient cell models including primary hepatocytes that were treated with 1'-hydroxymethyleugenol (OH-ME) as main phase I metabolite. Firstly, mass spectrometry showed a concentration-dependent formation of N2-MIE-dG as major DNA adduct, strongly correlating with SULT1A1 expression as attested in cells with and without human SULT1A1. ME-derived DNA damage activated mainly the ATR-mediated DNA damage response as shown by phosphorylation of CHK1 and histone 2AX, followed by p53 accumulation and CHK2 phosphorylation. Consistent with these findings, the DNA adducts decreased replication speed and caused replication fork stalling. OH-ME treatment reduced viability particularly in cell lines with wild-type p53 and triggered apoptotic cell death, which was rescued by pan-caspase-inhibition. Further experiments demonstrated mitochondrial apoptosis as major cell death pathway. ME-derived DNA damage caused upregulation of the p53-responsive genes NOXA and PUMA, Bax activation, and cytochrome c release followed by caspase-9 and caspase-3 cleavage. We finally demonstrated the crucial role of p53 for OH-ME triggered cell death as evidenced by reduced pro-apoptotic gene expression, strongly attenuated Bax activation and cell death inhibition upon genetic knockdown or pharmacological inhibition of p53. Taken together, our study demonstrates for the first time that ME-derived DNA damage causes replication stress and triggers mitochondrial apoptosis via the p53-Bax pathway.
    DOI:  https://doi.org/10.1038/s41419-022-05446-9
  18. Nat Metab. 2022 Nov 28.
    Mitochondrial RNA stimulates beige adipocyte development in young mice.
    Anh Cuong Hoang, László Sasi-Szabó, Tibor Pál, Tamás Szabó, Victoria Diedrich, Annika Herwig, Kathrin Landgraf, Antje Körner, Tamás Röszer.
      Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity.
    DOI:  https://doi.org/10.1038/s42255-022-00683-w
  19. Development. 2022 Dec 01. pii: dev200870. [Epub ahead of print]149(23):
    Mitochondrial respiration and dynamics of in vivo neural stem cells.
    Stavroula Petridi, Dnyanesh Dubal, Richa Rikhy, Jelle van den Ameele.
      Neural stem cells (NSCs) in the developing and adult brain undergo many different transitions, tightly regulated by extrinsic and intrinsic factors. While the role of signalling pathways and transcription factors is well established, recent evidence has also highlighted mitochondria as central players in NSC behaviour and fate decisions. Many aspects of cellular metabolism and mitochondrial biology change during NSC transitions, interact with signalling pathways and affect the activity of chromatin-modifying enzymes. In this Spotlight, we explore recent in vivo findings, primarily from Drosophila and mammalian model systems, about the role that mitochondrial respiration and morphology play in NSC development and function.
    Keywords:  Mitochondria; Mitochondrial morphology; Neural stem cell; Notch; Oxidative phosphorylation; Reactive oxygen species
    DOI:  https://doi.org/10.1242/dev.200870
  20. Hum Cell. 2022 Nov 29.
    Mitochondria: how eminent in ageing and neurodegenerative disorders?
    Chia Bamshad, Nima Najafi-Ghalehlou, Zahra Pourmohammadi-Bejarpasi, Kazuo Tomita, Yoshikazu Kuwahara, Tomoaki Sato, Alireza Feizkhah, Amaneh Mohammadi Roushnadeh, Mehryar Habibi Roudkenar.
      Numerous factors are implicated in the onset and progression of ageing and neurodegenerative disorders, with defects in cell energy supply and free radicals regulation designated as being the main functions of mitochondria and highly accentuated in plentiful studies. Hence, analysing the role of mitochondria as one of the main factors implicated in these disorders could undoubtedly come in handy with respect to disease prevention and treatment. In this review, first, we will explore how mitochondria account for neurodegenerative disorders and ageing and later will draw the various pathways contributing to mitochondrial dysfunction in their distinct way. Also, we will discuss the deviation-countering mechanisms, particularly mitophagy, a subset of autophagy known as a much larger cellular defence mechanism and regulatory system, along with its potential therapeutic effects. Last but not least, we will be highlighting the mitochondrial transfer experiments with animal models of neurodegenerative disorders.
    Keywords:  Ageing; Free radicals; Mitochondria; Mitochondrial transfer; Mitophagy; Neurodegenerative disorders
    DOI:  https://doi.org/10.1007/s13577-022-00833-y
  21. Science. 2022 Dec 02. 378(6623): 996-1000
    The human signal peptidase complex acts as a quality control enzyme for membrane proteins.
    Andrea Zanotti, João P L Coelho, Dinah Kaylani, Gurdeep Singh, Marina Tauber, Manuel Hitzenberger, Dönem Avci, Martin Zacharias, Robert B Russell, Marius K Lemberg, Matthias J Feige.
      Cells need to detect and degrade faulty membrane proteins to maintain homeostasis. In this study, we identify a previously unknown function of the human signal peptidase complex (SPC)-the enzyme that removes endoplasmic reticulum (ER) signal peptides-as a membrane protein quality control factor. We show that the SPC cleaves membrane proteins that fail to correctly fold or assemble into their native complexes at otherwise hidden cleavage sites, which our study reveals to be abundant in the human membrane proteome. This posttranslocational cleavage synergizes with ER-associated degradation to sustain membrane protein homeostasis and contributes to cellular fitness. Cryptic SPC cleavage sites thus serve as predetermined breaking points that, when exposed, help to target misfolded or surplus proteins for degradation, thereby maintaining a healthy membrane proteome.
    DOI:  https://doi.org/10.1126/science.abo5672
  22. Cereb Cortex. 2022 Nov 28. pii: bhac461. [Epub ahead of print]
    TDP-43 knockdown in mouse model of ALS leads to dsRNA deposition, gliosis, and neurodegeneration in the spinal cord.
    Ryan A Milstead, Christopher D Link, Zuoshang Xu, Charles A Hoeffer.
      Transactive response DNA binding protein 43 kilodaltons (TDP-43) is a DNA and RNA binding protein associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), primarily affecting motor neurons in the brain and spinal cord. Partial knockdown of TDP-43 expression in a mouse model (the amiR-TDP-43 mice) leads to progressive, age-related motor dysfunction, as observed in ALS patients. Work in Caenorhabditis elegans suggests that TDP-43 dysfunction can lead to deficits in chromatin processing and double-stranded RNA (dsRNA) accumulation, potentially activating the innate immune system and promoting neuroinflammation. To test this hypothesis, we used immunostaining to investigate dsRNA accumulation and other signs of CNS pathology in the spinal cords of amiR-TDP-43 mice. Compared with wild-type controls, TDP-43 knockdown animals show increases in dsRNA deposition in the dorsal and ventral horns of the spinal cord. Additionally, animals with heavy dsRNA expression show markedly increased levels of astrogliosis and microgliosis. Interestingly, areas of high dsRNA expression and microgliosis overlap with regions of heavy neurodegeneration, indicating that activated microglia could contribute to the degeneration of spinal cord neurons. This study suggests that loss of TDP-43 function could contribute to neuropathology by increasing dsRNA deposition and subsequent innate immune system activation.
    Keywords:  ALS; TDP-43; double-stranded RNA; immunostaining; neuropathology
    DOI:  https://doi.org/10.1093/cercor/bhac461
  23. Stem Cell Res. 2022 Nov 22. pii: S1873-5061(22)00329-4. [Epub ahead of print]65 102980
    Generation of a homozygous FIS1 knockout human embryonic stem cell line GIBHe015-B by CRISPR/Cas9 system.
    Mingquan Wang, Jun Tang, Tiancheng Zhou, Yuchan Mai, Yanling Zhu.
      The mitochondrial fission protein 1 (FIS1) is essential for mitochondrial division or fission and has been determined to mediate mitochondrial and peroxisomal fission. Other studies also found that FIS1 functions as an essential component of the mitophagy and apoptosis pathways in mammalian cells, suggesting that FIS1 has multiple important roles. Here, we generated homozygous FIS1 knockout human embryonic stem cells (hESCs) using the CRISPR/Cas9 system. This cell line exhibits normal karyotype, pluripotency, and trilineage differentiation potential, which could provide a useful cellular resource for exploring the functions of FIS1 and their implications in human health and diseases.
    DOI:  https://doi.org/10.1016/j.scr.2022.102980
  24. Cell Death Differ. 2022 Nov 30.
    PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment.
    Sonia Missiroli, Mariasole Perrone, Roberta Gafà, Francesco Nicoli, Massimo Bonora, Giampaolo Morciano, Caterina Boncompagni, Saverio Marchi, Magdalena Lebiedzinska-Arciszewska, Bianca Vezzani, Giovanni Lanza, Franz Kricek, Alessandro Borghi, Francesco Fiorica, Keisuke Ito, Mariusz R Wieckowski, Francesco Di Virgilio, Luigi Abelli, Paolo Pinton, Carlotta Giorgi.
      Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41418-022-01095-9
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