bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–07–28
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Preferred inhibition of pro-apoptotic Bak by BclxL via a two-step mechanism.
  2. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  3. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
  4. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
  5. Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.
  6. The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
  7. Germline regulation of the somatic mitochondrial stress response.
  8. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  9. Ring around the mitochondria.
  10. Complex roles for mitochondrial complexes in microglia.
  1. Cell Rep. 2024 Jul 22. pii: S2211-1247(24)00855-6. [Epub ahead of print]43(8): 114526
    Preferred inhibition of pro-apoptotic Bak by BclxL via a two-step mechanism.
    Kira D Leitl, Laura E Sperl, Franz Hagn.
      Bak is a pore-forming Bcl2 protein that induces apoptosis at the outer mitochondrial membrane, which can either proceed via Bak oligomerization or be inhibited by anti-apoptotic Bcl2 proteins, such as BclxL. BclxL is very efficient in inhibiting Bak pore formation, but the mechanistic basis of this preferred interaction has remained enigmatic. Here, we identify Bakα1 as a second binding site for BclxL and show that it specifically interacts with the Bcl2-homology (BH)3 binding groove of BclxL. The affinity between BclxL and Bakα1 is weaker than with Bak-BH3, suggesting that Bakα1, being exposed early in the pore-forming trajectory, transiently captures BclxL, which subsequently transitions to the proximal BH3 site. Bak variants where the initial transient interaction with BclxL is modulated show a markedly altered response to BclxL inhibition. This work contributes to a better mechanistic understanding of the fine-tuned interactions between different players of the Bcl2 protein family.
    Keywords:  CP: Cell biology; CP: Molecular biology; HDX-MS; NMR; apoptosis; inhibition; lipid nanodiscs; membrane
    DOI:  https://doi.org/10.1016/j.celrep.2024.114526
  2. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
  3. Nat Commun. 2024 Jul 21. 15(1): 6143
    ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
    Mailis Liiv, Annika Vaarmann, Dzhamilja Safiulina, Vinay Choubey, Ruby Gupta, Malle Kuum, Lucia Janickova, Zuzana Hodurova, Michal Cagalinec, Akbar Zeb, Miriam A Hickey, Yi-Long Huang, Nana Gogichaishvili, Merle Mandel, Mario Plaas, Eero Vasar, Jens Loncke, Tim Vervliet, Ting-Fen Tsai, Geert Bultynck, Vladimir Veksler, Allen Kaasik.
      Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
    DOI:  https://doi.org/10.1038/s41467-024-50502-x
  4. Nat Commun. 2024 Jul 22. 15(1): 6172
    Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
    Benjamin S Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A Adair, Ajit Elhance, Moemen Eltobgy, Francesca M Coan, Lexie Chafin, Jessica A Joseph, Alex Cornwell, Finny J Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S Bednash, James D Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S Lee, Bill B Chen, Rama K Mallampalli.
      The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50031-7
  5. iScience. 2024 Jul 19. 27(7): 110309
    Mitochondrial transfer between BMSCs and Müller promotes mitochondrial fusion and suppresses gliosis in degenerative retina.
    Xiaona Huang, Luodan A, Hui Gao, Juncai He, Lingling Ge, Zhe Cha, Hong Gong, Xi Lin, Huiting Li, Yongping Tang, Dan Jiang, Xiaotang Fan, Haiwei Xu.
      Mitochondrial dysfunction and Müller cells gliosis are significant pathological characteristics of retinal degeneration (RD) and causing blinding. Stem cell therapy is a promising treatment for RD, the recently accepted therapeutic mechanism is cell fusion induced materials transfer. However, whether materials including mitochondrial transfer between grafted stem cells and recipient's cells contribute to suppressing gliosis and mechanism are unclear. In present study, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) transferred mitochondria to Müller cells by cell fusion and tunneling nanotubes. BMSCs-derived mitochondria (BMSCs-mito) were integrated into mitochondrial network of Müller cells, improving mitochondrial function, reducing oxidative stress and gliosis, which protected visual function partially in the degenerative rat retina. RNA sequencing analysis revealed that BMSCs-mito increased mitochondrial DNA (mtDNA) content and facilitated mitochondrial fusion in damaged Müller cells. It suggests that mitochondrial transfer from BMSCs remodels Müller cells metabolism and suppresses gliosis; thus, delaying the degenerative progression of RD.
    Keywords:  cell biology; sensory neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.110309
  6. Nucleic Acids Res. 2024 Jul 22. pii: gkae645. [Epub ahead of print]
    The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
    Michele Brischigliaro, Annika Krüger, J Conor Moran, Hana Antonicka, Ahram Ahn, Eric A Shoubridge, Joanna Rorbach, Antoni Barrientos.
      The prokaryotic translation elongation factor P (EF-P) and the eukaryotic/archaeal counterparts eIF5A/aIF5A are proteins that serve a crucial role in mitigating ribosomal stalling during the translation of specific sequences, notably those containing consecutive proline residues (1,2). Although mitochondrial DNA-encoded proteins synthesized by mitochondrial ribosomes also contain polyproline stretches, an EF-P/eIF5A mitochondrial counterpart remains unidentified. Here, we show that the missing factor is TACO1, a protein causative of a juvenile form of neurodegenerative Leigh's syndrome associated with cytochrome c oxidase deficiency, until now believed to be a translational activator of COX1 mRNA. By using a combination of metabolic labeling, puromycin release and mitoribosome profiling experiments, we show that TACO1 is required for the rapid synthesis of the polyproline-rich COX1 and COX3 cytochrome c oxidase subunits, while its requirement is negligible for other mitochondrial DNA-encoded proteins. In agreement with a role in translation efficiency regulation, we show that TACO1 cooperates with the N-terminal extension of the large ribosomal subunit bL27m to provide stability to the peptidyl-transferase center during elongation. This study illuminates the translation elongation dynamics within human mitochondria, a TACO1-mediated biological mechanism in place to mitigate mitoribosome stalling at polyproline stretches during protein synthesis, and the pathological implications of its malfunction.
    DOI:  https://doi.org/10.1093/nar/gkae645
  7. Trends Cell Biol. 2024 Jul 20. pii: S0962-8924(24)00142-9. [Epub ahead of print]
    Germline regulation of the somatic mitochondrial stress response.
    Liankui Zhou, Ying Liu.
      Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.
    Keywords:  UPR(mt); cell-nonautonomous; germline; mitochondria; stress response
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.004
  8. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  9. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  10. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
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