bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒02‒12
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.
  2. Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.
  3. DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
  4. Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis.
  5. Oxidized mitochondrial DNA: a protective signal gone awry.
  6. RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.
  7. How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.
  1. 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
  2. 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
  3. 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
  4. 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
  5. Trends Immunol. 2023 Feb 02. pii: S1471-4906(23)00017-0. [Epub ahead of print]
    Oxidized mitochondrial DNA: a protective signal gone awry.
    Hongxu Xian, Michael Karin.
      Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1β, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.
    Keywords:  NLRP3 inflammasome; Ox-mtDNA; autoimmunity; cGAS–STING; cell-free DNA; immunopathology; inflammation; stressed mitochondria
    DOI:  https://doi.org/10.1016/j.it.2023.01.006
  6. J Biol Chem. 2023 Feb 07. pii: S0021-9258(23)00125-4. [Epub ahead of print] 102993
    RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.
    Joanne Ern Chi Soh, Akio Shimizu, Md Rasel Molla, Dimitar P Zankov, Le Kim Chi Nguyen, Mahbubur Rahman Khan, Wondwossen Wale Tesega, Si Chen, Misa Tojo, Yoshito Ito, Akira Sato, Masahito Hitosugi, Shigeru Miyagawa, Hisakazu Ogita.
      Heart failure is one of the leading causes of death worldwide. RhoA, a small GTPase, governs actin dynamics in various tissue and cell types, including cardiomyocytes; however, its involvement in cardiac function has not been fully elucidated. Here we generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice, which demonstrated a significantly shorter lifespan with left ventricular dilation and severely impaired ejection fraction. We found that the cardiac tissues of the cKO mice exhibited structural disorganization with fibrosis, and also exhibited enhanced senescence compared with control mice. In addition, we show that cardiomyocyte mitochondria were structurally abnormal in the aged cKO hearts. Clearance of damaged mitochondria by mitophagy was remarkably inhibited in both cKO cardiomyocytes and RhoA-knockdown HL-1 cultured cardiomyocytes. In RhoA-depleted cardiomyocytes, we reveal that the expression of Parkin, an E3 ubiquitin ligase that plays a crucial role in mitophagy, was reduced, and expression of N-Myc, a negative regulator of Parkin, was increased. We further reveal that the RhoA-Rho kinase axis induced N-Myc phosphorylation, which led to N-Myc degradation and Parkin upregulation. Re-expression of Parkin in RhoA-depleted cardiomyocytes restored mitophagy, reduced mitochondrial damage, attenuated cardiomyocyte senescence, and rescued cardiac function both in vitro and in vivo. Finally, we found that patients with idiopathic dilated cardiomyopathy (DCM) without causal mutations for DCM showed reduced cardiac expression of RhoA and Parkin. These results suggest that RhoA promotes Parkin-mediated mitophagy as an indispensable mechanism contributing to cardioprotection in the aging heart.
    Keywords:  Ras homolog gene family; cardiomyocyte; cardiomyopathy; member A (RhoA); mitophagy; parkin; senescence; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2023.102993
  7. Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00011-9. [Epub ahead of print]
    How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.
    Raquel Moreno-Loshuertos, Joaquín Marco-Brualla, Patricia Meade, Ruth Soler-Agesta, José A Enriquez, Patricio Fernández-Silva.
      Mitochondrial function generates an important fraction of the heat that contributes to cellular and organismal temperature maintenance, but the actual values of this parameter reached in the organelles is a matter of debate. The studies addressing this issue have reported divergent results: from detecting in the organelles the same temperature as the cell average or the incubation temperature, to increasing differences of up to 10 degrees above the incubation value. Theoretical calculations based on physical laws exclude the possibility of relevant temperature gradients between mitochondria and their surroundings. These facts have given rise to a conundrum or paradox about hot mitochondria. We have examined by Blue-Native electrophoresis, both in intact cells and in isolated organelles, the stability of respiratory complexes and supercomplexes at different temperatures to obtain information about their tolerance to heat stress. We observe that, upon incubation at values above 43 °C and after relatively short periods, respiratory complexes, and especially complex I and its supercomplexes, are unstable even when the respiratory activity is inhibited. These results support the conclusion that high temperatures (> 43 °C) cause damage to mitochondrial structure and function and question the proposal that these organelles can physiologically work at close to 50 °C.
    Keywords:  hyperthermia; mitochondria; respiratory complex; stability; supercomplex; temperature
    DOI:  https://doi.org/10.1016/j.mito.2023.02.002
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