bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒06‒18
fifteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
  2. A mitochondrial iron-responsive pathway regulated by DELE1.
  3. Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".
  4. An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation.
  5. Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
  6. Reversing the mitochondrial hex that bewitches NLRP3.
  7. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
  8. Aggregation prone Tau impairs mitochondrial import, which affects organelle morphology and neuronal complexity.
  9. Inner mitochondrial membrane fission protein, MTP18, serves as a mitophagy receptor to prevent apoptosis in oral cancer.
  10. MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.
  11. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
  12. The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
  13. Autophagy fuels mitochondrial function through regulation of iron metabolism in pancreatic cancer.
  14. Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response.
  15. How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
  1. EMBO J. 2023 Jun 12. e113908
    PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
    Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.
    Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)
    DOI:  https://doi.org/10.15252/embj.2023113908
  2. Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00413-6. [Epub ahead of print]83(12): 2059-2076.e6
    A mitochondrial iron-responsive pathway regulated by DELE1.
    Yusuke Sekine, Ryan Houston, Eva-Maria Eckl, Evelyn Fessler, Derek P Narendra, Lucas T Jae, Shiori Sekine.
      The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.
    Keywords:  DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.031
  3. Cell Rep. 2023 Jun 13. pii: S2211-1247(23)00643-5. [Epub ahead of print]42(6): 112632
    Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".
    Julia A Jones, Na Wei, Haissi Cui, Yi Shi, Guangsen Fu, Navin Rauniyar, Ryan Shapiro, Yosuke Morodomi, Nadine Berenst, Calin Dan Dumitru, Sachiko Kanaji, John R Yates, Taisuke Kanaji, Xiang-Lei Yang.
      Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.
    Keywords:  CP: Cell biology; CP: Molecular biology; aminoacyl-tRNA synthetase; cell survival; oxidative stress; stress response; transcriptional regulation; translation inhibition
    DOI:  https://doi.org/10.1016/j.celrep.2023.112632
  4. Mol Cell. 2023 Jun 08. pii: S1097-2765(23)00374-X. [Epub ahead of print]
    An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation.
    Stephanie Pei Tung Yiu, Cassie Zerbe, David Vanderwall, Edward L Huttlin, Michael P Weekes, Benjamin E Gewurz.
      Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis, and is associated with 200,000 cancers/year. EBV colonizes the human B cell compartment and periodically reactivates, inducing expression of 80 viral proteins. However, much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a map of EBV-host and EBV-EBV interactions in B cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein-coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Although UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo, and highlight BILF1 as a novel therapeutic target.
    Keywords:  MAVS; NLRP3 inflammasome; UFMylation; antiviral defense; gamma-herpesvirus; herpesvirus; interactome; mitochondrial-derived vesicles; viral evasion; virus/host interaction
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.018
  5. Sci Immunol. 2023 Jun 23. 8(84): eade7652
    Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
    Sung Hoon Baik, V Krishnan Ramanujan, Courtney Becker, Sarah Fett, David M Underhill, Andrea J Wolf.
      NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.
    DOI:  https://doi.org/10.1126/sciimmunol.ade7652
  6. Sci Immunol. 2023 Jun 23. 8(84): eadh2967
    Reversing the mitochondrial hex that bewitches NLRP3.
    Manasa Mellacheruvu, Grace M E P Lawrence, Stefan Emming, Kate Schroder.
      Hexokinase dissociation from mitochondria triggers calcium-induced oligomerization of VDAC within the outer mitochondrial membrane, leading to NLRP3 recruitment and inflammasome signaling (see related Research Article by Baik et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.adh2967
  7. Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):
    Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
    Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.
      Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.
    DOI:  https://doi.org/10.26508/lsa.202302127
  8. J Cell Sci. 2023 Jun 12. pii: jcs.260993. [Epub ahead of print]
    Aggregation prone Tau impairs mitochondrial import, which affects organelle morphology and neuronal complexity.
    Hope I Needs, Kevin A Wilkinson, Jeremy M Henley, Ian Collinson.
      Mitochondrial protein import is essential for organellar biogenesis, and thereby for the sufficient supply of cytosolic ATP-particularly important for cells with high energy demands like neurons. This study explores the prospect of import machinery perturbation as a cause of neurodegeneration instigated by the accumulation of aggregating proteins linked to disease. The aggregation-prone Tau variant (TauP301L) reduces the levels of components of the import machinery of the outer (TOM20) and inner membrane (TIM23) while associating with TOM40. Intriguingly, this interaction affects mitochondrial morphology, but not protein import or respiratory function; raising the prospect of an intrinsic rescue mechanism. Indeed, TauP301L induced the formation of tunnelling nanotubes (TNTs), potentially for the recruitment of healthy mitochondria from neighbouring cells and/or the disposal of mitochondria incapacitated by aggregated Tau. Consistent with this, inhibition of TNT formation (and rescue) reveals Tau-induced import impairment. In primary neuronal cultures, TauP301L induced morphological changes characteristic of neurodegeneration. Interestingly, these effects were mirrored in cells where the import sites were blocked artificially. Our results reveal a link between aggregation-prone Tau and defective mitochondrial import machinery relevant to disease.
    Keywords:  Mitochondria; Mitochondrial import; Mitochondrial morphology.; Neurodegeneration; Neuronal complexity; Tau
    DOI:  https://doi.org/10.1242/jcs.260993
  9. J Cell Sci. 2023 Jun 14. pii: jcs.259986. [Epub ahead of print]
    Inner mitochondrial membrane fission protein, MTP18, serves as a mitophagy receptor to prevent apoptosis in oral cancer.
    Debasna P Panigrahi, Prakash P Praharaj, Bishnu P Behera, Srimanta Patra, Shankargouda Patil, Birija Sankar Patro, Sujit K Bhutia.
      MTP18, an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology. Furthermore, MTP18 induces mitochondrial fission with subsequent mitophagy, functioning as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with LC3 through its LC3 interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibits that interaction, thus suppressing mitophagy. Moreover, Parkin/PINK1 deficiency abrogates mitophagy in MTP18-overexpressing FaDu cells. Upon exposure to CCCP, MTP18[mLIR]-FaDu cells show decreased TOM20 expression without affecting COX IV expression. Conversely, loss of Parkin/PINK1 results in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. The findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy.
    Keywords:  Apoptosis; MTP18; Mitochondrial fission; Mitophagy; Parkin
    DOI:  https://doi.org/10.1242/jcs.259986
  10. EMBO Rep. 2023 Jun 12. e56297
    MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.
    Xuecong Ren, Hengda Zhou, Yujie Sun, Hongying Fu, Yu Ran, Bing Yang, Fan Yang, Mikael Bjorklund, Suhong Xu.
      Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to fragmentation and loss of normal membrane potential in individual mitochondria. In this study, we show that MIRO-1 is stochastically elevated in individual fragmented mitochondria and is required for maintaining mitochondrial membrane potential. We further observe a higher level of membrane potential in fragmented mitochondria in fzo-1 mutants and wounded animals. Moreover, MIRO-1 interacts with VDAC-1, a crucial mitochondrial ion channel located in the outer mitochondrial membrane, and this interaction depends on the residues E473 of MIRO-1 and K163 of VDAC-1. The E473G point mutation disrupts their interaction, resulting in a reduction of the mitochondrial membrane potential. Our findings suggest that MIRO-1 regulates membrane potential and maintains mitochondrial activity and animal health by interacting with VDAC-1. This study provides insight into the mechanisms underlying the stochastic maintenance of membrane potential in fragmented mitochondria.
    Keywords:   Caenorhabditis elegans ; MIRO-1; VDAC-1; mitochondrial fragmentation; mitochondrial membrane potential (ΔΨm)
    DOI:  https://doi.org/10.15252/embr.202256297
  11. Cell Rep. 2023 Jun 12. pii: S2211-1247(23)00652-6. [Epub ahead of print]42(6): 112641
    Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
    Kiyoto Nishi, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo Frausto, Julia Ritterhoff, Timothy S McMillen, Ian Sweet, Yibin Wang, Chen Gao, Rong Tian.
      Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.
    Keywords:  CP: Metabolism; branched-chain amino acids; branched-chain keto acids; gluconeogenesis; mitochondrial pyruvate carrier; pyruvate
    DOI:  https://doi.org/10.1016/j.celrep.2023.112641
  12. Redox Biol. 2023 Jun 04. pii: S2213-2317(23)00160-X. [Epub ahead of print]64 102759
    The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
    Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N Feige, Umberto De Marchi.
      Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.
    Keywords:  C. elegans; Calcium signaling; MCU; Mitochondria; Redox biology; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2023.102759
  13. Autophagy. 2023 Jun 13. 1-2
    Autophagy fuels mitochondrial function through regulation of iron metabolism in pancreatic cancer.
    Subhadip Mukhopadhyay, Joel Encarnacion-Rosado, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of any cancer in the United States. Our previous work has shown that autophagy can promote PDAC progression. We recently established the importance of autophagy in regulating bioavailable iron to control mitochondrial metabolism in PDAC. We found that inhibition of autophagy in PDAC leads to mitochondrial dysfunction due to abrogation of succinate dehydrogenase complex iron sulfur subunit B (SDHB) expression. Additionally, we observed that cancer-associated fibroblasts (CAFs) can provide iron to autophagy-inhibited PDAC tumor cells, thereby increasing their resistance to autophagy inhibition. To impede such metabolic compensation, we used a low iron diet together with autophagy inhibition and demonstrated a significant improvement of tumor response in syngeneic PDAC models.Abbreviations: PDAC: Pancreatic ductal adenocarcinoma; CAFs: cancer-associated fibroblasts; SDHB: succinate dehydrogenase complex iron sulfur subunit B; ISCA1: iron sulfur cluster assembly protein 1; FPN: ferroportin; LIP: labile iron pool; FAC: ferric ammonium chloride; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation, IL6: interleukin 6; Fe-S: iron sulfur; ATP: adenosine triphosphate.
    Keywords:  Autophagy; cancer associated fibroblasts; iron metabolism; lysosome; mitochondria; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1080/15548627.2023.2223473
  14. J Biol Chem. 2023 Jun 09. pii: S0021-9258(23)01934-8. [Epub ahead of print] 104906
    Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response.
    Ivan Tan, Shengli Xu, Jianxin Huo, Yuhan Huang, Hong-Hwa Lim, Kong-Peng Lam.
      The tumor suppressor Liver Kinase B1 (LKB1) is a multifunctional serine/threonine protein kinase that regulates cell metabolism, polarity and growth and is associated with Peutz-Jeghers Syndrome and cancer predisposition. The LKB1 gene comprises 10 exons and 9 introns. Three spliced LKB1 variants have been documented, and they reside mainly in the cytoplasm, although two possess a nuclear-localization sequence (NLS) and are able to shuttle into the nucleus. Here, we report the identification of a fourth and novel LKB1 isoform that is, interestingly, targeted to the mitochondria. We show that this mitochondria-localized LKB1 (mLKB1) is generated from alternative splicing in the 5' region of the transcript and translated from an alternative initiation codon encoded by a previously unknown exon 1b (131bp) hidden within the long intron 1 of LKB1 gene. We found by replacing the N-terminal NLS of the canonical LKB1 isoform, the N-terminus of the alternatively spliced mLKB1 variant encodes a mitochondrial transit peptide that allows it to localize to the mitochondria. We further demonstrate that mLKB1 colocalizes histologically with mitochondria-resident ATP Synthase and NAD-dependent deacetylase sirtuin-3, mitochondrial (SIRT3) and that its expression is rapidly and transiently upregulated by oxidative stress. We conclude that this novel LKB1 isoform, mLKB1, plays a critical role in regulating mitochondrial metabolic activity and oxidative stress response.
    Keywords:  DNA damage; cellular localization; exon; intron; isoforms; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jbc.2023.104906
  15. Trends Endocrinol Metab. 2023 Jun 13. pii: S1043-2760(23)00107-8. [Epub ahead of print]
    How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
    Mohamed A Eldeeb, Andrea Soumbasis, Edward A Fon.
      Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently elicit mitophagy without the loss of mitochondrial membrane potential.
    Keywords:  PINK1; TOM complex; mitochondrial import; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1016/j.tem.2023.05.005
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