bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒09‒11
ten papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
  2. DarT-mediated mtDNA damage induces dynamic reorganization and selective segregation of mitochondria.
  3. Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker.
  4. STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
  5. Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
  6. Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.
  7. A brown fat-selective mechanism of mitochondrial calcium import?
  8. From dynamin related proteins structures and oligomers to membrane fusion mediated by Mitofusins.
  9. Non-conventional mitochondrial permeability transition: Its regulation by mitochondrial dynamics.
  10. The iron-sulfur cluster assembly (ISC) protein Iba57 executes a tetrahydrofolate-independent function in mitochondrial [4Fe-4S] protein maturation.
  1. Cell Metab. 2022 Aug 30. pii: S1550-4131(22)00353-9. [Epub ahead of print]
    Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
    Nicholas Borcherding, Wentong Jia, Rocky Giwa, Rachael L Field, John R Moley, Benjamin J Kopecky, Mandy M Chan, Bin Q Yang, Jessica M Sabio, Emma C Walker, Omar Osorio, Andrea L Bredemeyer, Terri Pietka, Jennifer Alexander-Brett, Sharon Celeste Morley, Maxim N Artyomov, Nada A Abumrad, Joel Schilling, Kory Lavine, Clair Crewe, Jonathan R Brestoff.
      Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.
    Keywords:  CD36; EXT1; aging; beige fat; brown adipose tissue; cell-free mitochondria; fatty acids; heparan sulfate; horizontal mitochondria transfer; intercellular mitochondria transfer; lipids; macrophage; mitochondria; obesity; palmitate; white adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.010
  2. J Cell Biol. 2022 Oct 03. pii: e202205104. [Epub ahead of print]221(10):
    DarT-mediated mtDNA damage induces dynamic reorganization and selective segregation of mitochondria.
    Nitish Dua, Akshaya Seshadri, Anjana Badrinarayanan.
      Mitochondria are dynamic organelles that play essential roles in cell growth and survival. Processes of fission and fusion are critical for the distribution, segregation, and maintenance of mitochondria and their genomes (mtDNA). While recent work has revealed the significance of mitochondrial organization for mtDNA maintenance, the impact of mtDNA perturbations on mitochondrial dynamics remains less understood. Here, we develop a tool to induce mitochondria-specific DNA damage using a mitochondrial-targeted base modifying bacterial toxin, DarT. Following damage, we observe dynamic reorganization of mitochondrial networks, likely driven by mitochondrial dysfunction. Changes in the organization are associated with the loss of mtDNA, independent of mitophagy. Unexpectedly, perturbation to exonuclease function of mtDNA replicative polymerase, Mip1, results in rapid loss of mtDNA. Our data suggest that, under damage, partitioning of defective mtDNA and organelle are de-coupled, with emphasis on mitochondrial segregation independent of its DNA. Together, our work underscores the importance of genome maintenance on mitochondrial function, which can act as a modulator of organelle organization and segregation.
    DOI:  https://doi.org/10.1083/jcb.202205104
  3. PNAS Nexus. 2022 Sep;1(4): pgac147
    Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker.
    Jude M Phillip, Ran Lin, Andrew Cheetham, David Stern, Yukang Li, Yuzhu Wang, Han Wang, David Rini, Honggang Cui, Jeremy D Walston, Peter M Abadir.
      Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker-Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.
    Keywords:  Losartan; angiotensin system; mitochondria; mitochondrial targeting
    DOI:  https://doi.org/10.1093/pnasnexus/pgac147
  4. iScience. 2022 Sep 16. 25(9): 104923
    STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
    Hyunmi Kim, Soo Jung Park, Ilo Jou.
      Although it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, the functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has a critical role in mitochondrial dynamics. Moreover, mitochondrial accumulation of STAT6 in response to hypoxic conditions reveals that STAT6 is a regulator of mitochondrial processes including fusion/fission mechanisms.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2022.104923
  5. iScience. 2022 Sep 16. 25(9): 104920
    Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
    Pernille Bülow, Anupam Patgiri, Victor Faundez.
      The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.
    Keywords:  Biological Sciences; Cell Biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104920
  6. iScience. 2022 Sep 16. 25(9): 104941
    Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.
    Fannie W Chen, Joanna P Davies, Raul Calvo, Jagruti Chaudhari, Georgia Dolios, Mercedes K Taylor, Samarjit Patnaik, Jean Dehdashti, Rebecca Mull, Patricia Dranchack, Amy Wang, Xin Xu, Emma Hughes, Noel Southall, Marc Ferrer, Rong Wang, Juan J Marugan, Yiannis A Ioannou.
      Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.
    Keywords:  Cell biology; Cellular neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104941
  7. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00354-0. [Epub ahead of print]34(9): 1231-1233
    A brown fat-selective mechanism of mitochondrial calcium import?
    Janane F Rahbani, Lawrence Kazak.
      In this issue of Cell Metabolism, Xue et al. propose that the mitochondrial calcium uniporter (MCU) binds uncoupling protein 1 (UCP1) via the MCU regulator (EMRE) to form a protein complex that the authors term the "thermoporter." Through gain- and loss-of-function experiments, the authors infer that the thermoporter promotes calcium influx into the mitochondrial matrix to enhance NADH production, which supports thermogenesis in brown adipose tissue (BAT).
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.011
  8. Biochim Biophys Acta Bioenerg. 2022 Aug 31. pii: S0005-2728(22)00383-8. [Epub ahead of print] 148913
    From dynamin related proteins structures and oligomers to membrane fusion mediated by Mitofusins.
    Mohammad Ozeir, Mickael M Cohen.
      Mitochondria assemble in a highly dynamic network where interconnected tubules evolve in length and size through regulated cycles of fission and fusion of mitochondrial membranes thereby adapting to cellular needs. Mitochondrial fusion and fission processes are mediated by specific sets of mechano-chemical large GTPases that belong to the Dynamin-Related Proteins (DRPs) super family. DRPs bind to cognate membranes and auto-oligomerize to drive lipid bilayers remodeling in a nucleotide dependent manner. Although structural characterization and mechanisms of DRPs that mediate membrane fission are well established, the capacity of DRPs to mediate membrane fusion is only emerging. In this review, we discuss the distinct structures and mechanisms of DRPs that trigger the anchoring and fusion of biological membranes with a specific focus on mitofusins that are dedicated to the fusion of mitochondrial outer membranes. In particular, we will highlight oligomeric assemblies of distinct DRPs and confront their mode of action against existing models of mitofusins assemblies with emphasis on recent biochemical, structural and computational reports. As we will see, the literature brings valuable insights into the presumed macro-assemblies mitofusins may form during anchoring and fusion of mitochondrial outer membranes.
    Keywords:  DRPs; Mitochondria; Mitochondrial dynamics; Mitofusins
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148913
  9. Biochim Biophys Acta Bioenerg. 2022 Sep 02. pii: S0005-2728(22)00384-X. [Epub ahead of print] 148914
    Non-conventional mitochondrial permeability transition: Its regulation by mitochondrial dynamics.
    Yisang Yoon, Hakjoo Lee, Marilen Federico, Shey-Shing Sheu.
      Mitochondrial permeability transition (MPT) is a phenomenon that the inner mitochondrial membrane (IMM) loses its selective permeability, leading to mitochondrial dysfunction and cell injury. Electrophysiological evidence indicates the presence of a mega-channel commonly called permeability transition pore (PTP) whose opening is responsible for MPT. However, the molecular identity of the PTP is still under intensive investigations and debates, although cyclophilin D that is inhibited by cyclosporine A (CsA) is the established regulatory component of the PTP. PTP can also open transiently and functions as a rapid mitochondrial Ca2+ releasing mechanism. Mitochondrial fission and fusion, the main components of mitochondrial dynamics, control the number and size of mitochondria, and have been shown to play a role in regulating MPT directly or indirectly. Studies by us and others have indicated the potential existence of a form of transient MPT that is insensitive to CsA. This "non-conventional" MPT is regulated by mitochondrial dynamics and may serve a protective role possibly by decreasing the susceptibility for a frequent or sustained PTP opening; hence, it may have a therapeutic value in many disease conditions involving MPT.
    Keywords:  Mitochondrial dynamics; Mitochondrial permeability transition; Non-conventional mitochondrial permeability transition; Permeability transition pore
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148914
  10. J Biol Chem. 2022 Sep 05. pii: S0021-9258(22)00908-5. [Epub ahead of print] 102465
    The iron-sulfur cluster assembly (ISC) protein Iba57 executes a tetrahydrofolate-independent function in mitochondrial [4Fe-4S] protein maturation.
    Ulrich Mühlenhoff, Benjamin Dennis Weiler, Franziska Nadler, Robert Millar, Isabell Kothe, Sven-Andreas Freibert, Florian Altegoer, Gert Bange, Roland Lill.
      Mitochondria harbor the bacteria-inherited iron-sulfur cluster assembly (ISC) machinery to generate [2Fe-2S] and [4Fe-4S] proteins. In yeast, assembly of [4Fe-4S] proteins specifically involves the ISC proteins Isa1, Isa2, Iba57, Bol3, and Nfu1. Functional defects in their human equivalents cause the multiple mitochondrial dysfunction syndromes (MMDS), severe disorders with a broad clinical spectrum. The bacterial Iba57 ancestor YgfZ was described to require tetrahydrofolate (THF) for its function in the maturation of selected [4Fe-4S] proteins. Both YgfZ and Iba57 are structurally related to an enzyme family catalyzing THF-dependent one-carbon transfer reactions including GcvT of the glycine cleavage system. On this basis, a universally conserved folate requirement in ISC-dependent [4Fe-4S] protein biogenesis was proposed. To test this idea for mitochondrial Iba57, we performed genetic and biochemical studies in S. cerevisiae, and we solved the crystal structure of Iba57 from the thermophilic fungus Chaetomium thermophilum. We provide three lines of evidence for the THF independence of the Iba57-catalyzed [4Fe-4S] protein assembly pathway. First, yeast mutants lacking folate show no defect in mitochondrial [4Fe-4S] protein maturation. Second, the 3D structure of Iba57 lacks many of the side chain contacts to THF as defined in GcvT, and the THF binding pocket is constricted. Third, mutations in conserved Iba57 residues that are essential for THF-dependent catalysis in GcvT do not impair Iba57 function in vivo, in contrast to an exchange of the invariant, surface-exposed cysteine residue. We conclude that mitochondrial Iba57, despite structural similarities to both YgfZ and THF-binding proteins, does not utilize folate for its function.
    Keywords:  Iron-sulfur protein; crystallography; folate; iron-sulfur cluster assembly; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.jbc.2022.102465
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