bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–02–12
eight papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
  2. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
  3. The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
  4. Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats.
  5. DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
  6. Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
  7. Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.
  8. Contribution of NRF2 to sulfur metabolism and mitochondrial activity.
  1. Nature. 2023 Feb 08.
    Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
    Joe Nassour, Lucia Gutierrez Aguiar, Adriana Correia, Tobias T Schmidt, Laura Mainz, Sara Przetocka, Candy Haggblom, Nimesha Tadepalle, April Williams, Maxim N Shokhirev, Semih C Akincilar, Vinay Tergaonkar, Gerald S Shadel, Jan Karlseder.
      Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations1,2. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.
    DOI:  https://doi.org/10.1038/s41586-023-05710-8
  2. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00003-7. [Epub ahead of print]35(2): 345-360.e7
    Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
    Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee.
      Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
    Keywords:  FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.003
  3. Nat Commun. 2023 Feb 06. 14(1): 638
    The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
    Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.
      The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.
    DOI:  https://doi.org/10.1038/s41467-023-36298-2
  4. Nat Commun. 2023 Feb 11. 14(1): 766
    Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats.
    Noble Kumar Talari, Ushodaya Mattam, Niroj Kumar Meher, Arun Kumar Paripati, Kalyankar Mahadev, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.
      Mitochondria empower the liver to regulate lipid homeostasis by enabling fatty acid oxidation during starvation and lipogenesis during nutrient-rich conditions. It is unknown if mitochondria can seamlessly regulate these two distinct processes or if two discrete populations of mitochondria achieve these two functions in the liver. For the first time in the liver, we report the isolation of two distinct populations of mitochondria from male Wistar rats on an ad-libitum diet: cytoplasmic mitochondria and lipid droplet-associated mitochondria. Our studies show that while lipid droplet mitochondria exhibit higher fatty acid oxidation and are marked by enhanced levels of pACC2, MFN2, and CPT1 activity, cytoplasmic mitochondria are associated with higher respiration capacity. Notably, lipid droplet-associated mitochondria isolated from a non-alcoholic fatty liver disease (NAFLD) rat model are compromised for fatty acid oxidation. We demonstrate the importance of functional segregation of mitochondria as any aberration in lipid droplet-associated mitochondria may lead to NAFLD.
    DOI:  https://doi.org/10.1038/s41467-023-36432-0
  5. J Cell Sci. 2023 Feb 01. pii: jcs260370. [Epub ahead of print]136(3):
    DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
    Gabriella L Robertson, Stellan Riffle, Mira Patel, Caroline Bodnya, Andrea Marshall, Heather K Beasley, Edgar Garza-Lopez, Jianqiang Shao, Zer Vue, Antentor Hinton, Maria S Stoll, Sholto de Wet, Rensu P Theart, Ram Prosad Chakrabarty, Ben Loos, Navdeep S Chandel, Jason A Mears, Vivian Gama.
      Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.
    Keywords:  Cristae; DRP1; Fibroblast; Glycolysis; Mitochondria; Oxidative phosphorylation; Peroxisome
    DOI:  https://doi.org/10.1242/jcs.260370
  6. J Cell Sci. 2023 Feb 06. pii: jcs.260612. [Epub ahead of print]
    Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
    Stephen M Coscia, Cameron P Thompson, Qing Tang, Elana E Baltrusaitis, Joseph A Rhodenhiser, Omar A Quintero-Carmona, E Michael Ostap, Melike Lakadamyali, Erika L F Holzbaur.
      Mitochondrial homeostasis requires a dynamic balance of fission and fusion. The actin cytoskeleton promotes fission; we find that the mitochondrially-localized myosin, Myosin 19 (Myo19), is integral to this process. Myo19 knock-down induces mitochondrial elongation, while Myo19 overexpression induces fragmentation. This mitochondrial fragmentation is blocked by a Myo19 mutation predicted to inhibit ATPase activity and strong actin binding but not by mutations predicted to affect the motor's working stroke that preserve ATPase activity. Super-resolution imaging indicates a dispersed localization of Myo19 on mitochondria, which we find to be dependent on metaxins. These observations suggest that Myo19 acts as a dynamic actin-binding tether that facilitates mitochondrial fragmentation. Myo19-driven fragmentation is blocked by depletion of either the endoplasmic reticulum (ER)-anchored formin INF2-CAAX or the mitochondrially-localized F-actin nucleator Spire1C, which together polymerize actin at sites of mito-ER contact for fission. These observations imply that Myo19 promotes fission by stabilizing mito-ER contacts; we used a split-luciferase system to demonstrate a reduction in these contacts following Myo19 depletion. Our data support a model in which Myo19 tethers mitochondria to ER-associated actin to promote mitochondrial fission.
    Keywords:  Actin; Endoplasmic reticulum; Fission; Mito-ER contacts; Mitochondria; Myosin
    DOI:  https://doi.org/10.1242/jcs.260612
  7. Oncogene. 2023 Feb 09.
    Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.
    Linmeng Han, Chunyu Zhang, Danni Wang, Jiaqi Zhang, Qiqi Tang, Mulin Jun Li, Michael N Sack, Lingdi Wang, Lu Zhu.
      Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.
    DOI:  https://doi.org/10.1038/s41388-023-02621-w
  8. Redox Biol. 2023 Feb 02. pii: S2213-2317(23)00025-3. [Epub ahead of print]60 102624
    Contribution of NRF2 to sulfur metabolism and mitochondrial activity.
    Md Morshedul Alam, Akihiro Kishino, Eunkyu Sung, Hiroki Sekine, Takaaki Abe, Shohei Murakami, Takaaki Akaike, Hozumi Motohashi.
      NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation.
    Keywords:  Cysteine; Cystine; Mitochondria; Mitochondrial membrane potential; Persulfide; xCT
    DOI:  https://doi.org/10.1016/j.redox.2023.102624
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