bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2024–12–22
eleven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
  2. Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
  3. Human mitochondrial RNA polymerase structures reveal transcription start-site and slippage mechanism.
  4. Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
  5. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
  6. A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.
  7. Cellular RNA interacts with MAVS to promote antiviral signaling.
  8. Elevated levels of intracellular RNA lariats suppress the antiviral response.
  9. Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
  10. Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
  11. Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.
  1. Aging Cell. 2024 Dec 16. e14402
    Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
    Amy R Vandiver, Alejandro Torres, Amberly Sanden, Thang L Nguyen, Jasmine Gasilla, Mary T Doan, Vahan Martirosian, Austin Hoang, Jonathan Wanagat, Michael A Teitell.
      The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.
    Keywords:  aging; iPSC; mitochondria; mtDNA mutation
    DOI:  https://doi.org/10.1111/acel.14402
  2. J Cell Sci. 2024 Dec 20. pii: jcs.263459. [Epub ahead of print]
    Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
    Yuli Buckley, Maria S K Stoll, Charles L Hoppel, Jason A Mears.
      In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress and uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered ETC activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.
    Keywords:  Bioenergetics; Fis1; Ionizing radiation; Mitochondrial fission; MtDNA
    DOI:  https://doi.org/10.1242/jcs.263459
  3. bioRxiv. 2024 Dec 02. pii: 2024.12.02.626445. [Epub ahead of print]
    Human mitochondrial RNA polymerase structures reveal transcription start-site and slippage mechanism.
    Jiayu Shen, Quinten Goovaerts, Yogeeshwar Ajjugal, Brent De Wijngaert, Kalyan Das, Smita S Patel.
      Human mitochondrial RNA polymerase (POLRMT) and protein factors TFAM and TFB2M assemble on mitochondrial DNA promoters to initiate promoter-specific transcription. We present cryo-EM structures of two initiation complexes, IC3 and slipped-IC3, with fully resolved transcription bubbles containing RNA transcripts starting from +1 and -1 positions, respectively. These structures reveal the mechanisms of promoter melting, start site selection, and slippage synthesis. Promoter melting begins at -4 with base-specific interactions of -4 and -3 template guanines with POLRMT and -1 non-template adenine with TFB2M, stabilizing the bubble and facilitating initiation from +1. Slippage occurs when a synthesized 2-mer RNA shifts to -1; the -1 position is not an alternative start-site. The conserved non-template sequence (-1)AAA(+2) is recognized by a non-template stabilizing loop (K153LDPRSGGVIKPP165) and Y209 from TFB2M and W1026 of POLRMT. The initiation complex on cryo-EM grids exist in equilibrium with apo and dimeric POLRMTs, whose relative concentrations may regulate transcription initiation.
    Keywords:  POLRMT; TFAM; TFB2M; abortive synthesis; promoter melting; transcription initiation
    DOI:  https://doi.org/10.1101/2024.12.02.626445
  4. Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]
    Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
    Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.
      Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-5278203/v1
  5. Nat Metab. 2024 Dec;6(12): 2319-2337
    Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
    Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.
      The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.
    DOI:  https://doi.org/10.1038/s42255-024-01174-w
  6. Neurosci Insights. 2024 ;19 26331055241305151
    A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.
    Manohar Kodavati, Muralidhar L Hegde.
      Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.
    Keywords:  ALS; DNA damage; DNA ligase; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1177/26331055241305151
  7. Science. 2024 Dec 20. 386(6728): eadl0429
    Cellular RNA interacts with MAVS to promote antiviral signaling.
    Nandan S Gokhale, Russell K Sam, Kim Somfleth, Matthew G Thompson, Daphnée M Marciniak, Julian R Smith, Emmanuelle Genoyer, Julie Eggenberger, Lan H Chu, Moonhee Park, Steve Dvorkin, Andrew Oberst, Stacy M Horner, Shao-En Ong, Michael Gale, Ram Savan.
      Antiviral signaling downstream of RIG-I-like receptors (RLRs) proceeds through a multi-protein complex organized around the adaptor protein mitochondrial antiviral signaling protein (MAVS). Protein complex function can be modulated by RNA molecules that provide allosteric regulation or act as molecular guides or scaffolds. We hypothesized that RNA plays a role in organizing MAVS signaling platforms. We found that MAVS, through its central intrinsically disordered domain, directly interacted with the 3' untranslated regions of cellular messenger RNAs. Elimination of RNA by ribonuclease treatment disrupted the MAVS signalosome, including RNA-modulated MAVS interactors that regulate RLR signaling and viral restriction, and inhibited phosphorylation of transcription factors that induce interferons. This work uncovered a function for cellular RNA in promoting signaling through MAVS and highlights generalizable principles of RNA regulatory control of immune signaling complexes.
    DOI:  https://doi.org/10.1126/science.adl0429
  8. bioRxiv. 2024 Dec 08. pii: 2024.12.07.627371. [Epub ahead of print]
    Elevated levels of intracellular RNA lariats suppress the antiviral response.
    Chaorui Duan, Luke Buerer, Cory Bowers, Allison J Taggart, Mara H O'Brien, Sarah Gunasekera, Chien-Ling Lin, Jing Wang, Jonathan P Staley, Alger M Fredericks, Sean F Monaghan, Anastasia Welch, Nathaniel E Clark, Daxing Gao, Nico Marr, Shen-Ying Zhang, Jean-Laurent Casanova, William G Fairbrother.
      Recent studies report the genetic loss of the lariat debranching enzyme ( DBR1 ) activity increases susceptibility to viral infection. Here, we show that more than 25% of human introns contain large hairpin structures created by the folding of two Alu elements inserted in opposite orientation. In wildtype cells, this large reservoir of endogenous dsRNA is efficiently degraded. In DBR1 -null cells, lariats accumulate in the cytosol and dsRNA becomes enriched. We demonstrate how the chronic exposure to these lariats attenuates the dsRNA sensors, reducing the response of the MDA5, RIG-I, RNase L and PKR sensing pathways. We observe evidence for both attenuation and endogenous dsRNA in anti-viral response and viral evasion. Lariats are transiently elevated during infection (e.g. HSV-1, influenza, KSHV). The HSV-1 genome expresses multiple, stable lariats that may attenuate dsRNA sensors during latency.
    HIGHLIGHTS: Intronic inverted repeat Alu elements constitute largest source of endogenous dsRNA. In the absence of DBR1 , lariats accumulate in the cytoplasm and form dsRNA. Chronic exposure to endogenous dsRNA in a DBR1 -depleted environment desensitizes the dsRNA sensing pathway. ICP0 intron 1 of HSV-1 has a highly-structured stable lariat.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2024.12.07.627371
  9. Autophagy. 2024 Dec 15.
    Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
    Isabel Gordaliza-Alaguero, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Laura Villarreal, Gianluca Arauz-Garofalo, Marina Gay, Marta Martinez-Vicente, Jorge Seco, Pau Martin-Malpartida, Marta Vilaseca, María J Macías, Manuel Palacin, Saška Ivanova, Antonio Zorzano.
      MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA. HA-affinity isolation followed by mass spectrometry identified potential interactors of MFN1 and MFN2. A substantial proportion of interactors were common for MFN1 and MFN2 and were regulated by nutrient deprivation. We validated novel ER and endosomal partners of MFN1 and/or MFN2 with a potential role in interorganelle communication. We characterized RAB5C (RAB5C, member RAS oncogene family) as an endosomal modulator of mitochondrial homeostasis, and SLC27A2 (solute carrier family 27 (fatty acid transporter), member 2) as a novel partner of MFN2 relevant in autophagy. We conclude that MFN proteins participate in nutrient-modulated pathways involved in organelle communication and autophagy.
    Keywords:  Autophagosomes; endosomes; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2024.2440843
  10. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02578-X. [Epub ahead of print] 108076
    Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
    Tadato Ban, Kimiya Kuroda, Mitsuhiro Nishigori, Keisuke Yamashita, Keisuke Ohta, Takumi Koshiba.
      Prohibitins (PHBs) are ubiquitously expressed proteins in the mitochondrial inner membrane (MIM) that provide membrane scaffolds for both mitochondrial proteins and phospholipids. Eukaryotic PHB complexes contain two highly homologous PHB subunits, PHB1 and PHB2, which are involved in various cellular processes, including metabolic control through the regulation of mitochondrial dynamics and integrity. Their mechanistic actions at the molecular level, however, particularly those of PHB1, remain poorly understood. To gain insight into the mechanistic actions of PHB1, we established an overexpression system for the full-length recombinant protein using silkworm larvae and characterized its biophysical properties in vitro. Using recombinant PHB1 proteoliposomes reconstituted into MIM-mimicking phospholipids, we found that PHB1 forms an oligomer via its carboxy-terminal coiled-coil region. A proline substitution into the PHB1 coiled-coil collapsed its well-ordered oligomeric state, and its destabilization correlated with mitochondrial morphologic defects. Negative-staining electron microscopy revealed that homotypic PHB1-PHB1 interactions via the coiled-coil also induced liposome tethering with remodeling of the lipid membrane structure. We clarified that PHB1 promotes membrane fusion mediated by optic atrophy 1 (OPA1), a key regulator of MIM fusion. Additionally, the presence of PHB1 reduces the dependency of lipids and OPA1 for completing the fusion process. Our in vitro study provides structural insight into how the mitochondrial scaffold plays a crucial role in regulating mitochondrial dynamics. Modulating the structure and/or function of PHB1 may offer new therapeutic potential, not only for mitochondrial dysfunction but also for other cell-related disorders.
    Keywords:  Coiled-coil; Prohibitin 1; membrane fusion; mitochondria; proteoliposomes
    DOI:  https://doi.org/10.1016/j.jbc.2024.108076
  11. Science. 2024 Dec 20. 386(6728): eadp6547
    Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.
    Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, Huan Ma.
      Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TCmito), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TCnuc). We demonstrated that E-TCmito repurposes molecules traditionally associated with E-TCnuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TCmito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TCmito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.
    DOI:  https://doi.org/10.1126/science.adp6547
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