bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–02–25
six papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
  2. MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
  3. Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
  4. Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
  5. ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
  6. Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.
  1. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772
    Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
    Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.
      The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
    Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2024.113772
  2. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874
    MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
    Kostas Tokatlidis.
      Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.
    DOI:  https://doi.org/10.1016/j.celrep.2024.113874
  3. Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805
    Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
    Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.
      The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.
    Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113805
  4. Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2311160121
    Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
    Rui Wang, Huan Lei, Hongxiang Wang, Lei Qi, Yu'e Liu, Yunhui Liu, Yufeng Shi, Juxiang Chen, Qing-Tao Shen.
      Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.
    Keywords:  cryo-electron tomography; glioblastoma; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1073/pnas.2311160121
  5. Nat Commun. 2024 Feb 17. 15(1): 1460
    ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
    Taeko Sasaki, Yasuharu Kushida, Takuya Norizuki, Hidetaka Kosako, Ken Sato, Miyuki Sato.
      Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.
    DOI:  https://doi.org/10.1038/s41467-024-45863-2
  6. iScience. 2024 Mar 15. 27(3): 109078
    Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.
    Valérie Voorsluijs, Francesco Avanzini, Gianmaria Falasco, Massimiliano Esposito, Alexander Skupin.
      Energy transduction is central to living organisms, but the impact of enzyme regulation and signaling on its thermodynamic efficiency is generally overlooked. Here, we analyze the efficiency of ATP production by the tricarboxylic acid cycle and oxidative phosphorylation, which generate most of the chemical energy in eukaryotes. Calcium signaling regulates this pathway and can affect its energetic output, but the concrete energetic impact of this cross-talk remains elusive. Calcium enhances ATP production by activating key enzymes of the tricarboxylic acid cycle while calcium homeostasis is ATP-dependent. We propose a detailed kinetic model describing the calcium-mitochondria cross-talk and analyze it using nonequilibrium thermodynamics: after identifying the effective reactions driving mitochondrial metabolism out of equilibrium, we quantify the mitochondrial thermodynamic efficiency for different conditions. Calcium oscillations, triggered by extracellular stimulation or energy deficiency, boost the thermodynamic efficiency of mitochondrial metabolism, suggesting a compensatory role of calcium signaling in mitochondrial bioenergetics.
    Keywords:  Biological sciences; Human metabolism; Molecular biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109078
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