bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–09–08
twelve papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
  2. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  3. Mitochondrial transplants to treat mitochondrial dysfunction.
  4. Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
  5. Older age reduces mtDNA mutation inheritance.
  6. Metabolic regulation of the mitochondrial immune checkpoint.
  7. Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
  8. Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
  9. Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
  10. Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
  11. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  12. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
  1. Science. 2024 Sep 06. 385(6713): 1086-1090
    In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
    Lea Dietrich, Ahmed-Noor A Agip, Christina Kunz, Andre Schwarz, Werner Kühlbrandt.
      Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate Polytomella by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F1 head. The Polytomella ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.
    DOI:  https://doi.org/10.1126/science.adp4640
  2. Nat Metab. 2024 Sep 02.
    Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
    Ritsuko Nakai, Stella Varnum, Rachael L Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J Krysa, Eva F Cohen, Nicholas Borcherding, Russell P Saneto, Rick C Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R Brestoff.
      Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
    DOI:  https://doi.org/10.1038/s42255-024-01125-5
  3. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  4. Nat Commun. 2024 Sep 03. 15(1): 7677
    Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
    Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.
      Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.
    DOI:  https://doi.org/10.1038/s41467-024-50632-2
  5. Nat Aging. 2024 Sep 04.
    Older age reduces mtDNA mutation inheritance.
    Polyxeni Papadea, Nils-Göran Larsson.
      
    DOI:  https://doi.org/10.1038/s43587-024-00701-4
  6. Oncoimmunology. 2024 ;13(1): 2394247
    Metabolic regulation of the mitochondrial immune checkpoint.
    David C Montrose, Suchandrima Saha, Lorenzo Galluzzi.
      Disrupting mitochondrial function in malignant cells is a promising strategy to enhance anticancer immunity. We have recently demonstrated that depriving colorectal cancer cells of serine results in mitochondrial dysfunction coupled with the cytosolic accumulation of mitochondrial DNA and consequent activation of CGAS- and STING-dependent tumor-targeting immune responses.
    Keywords:  Apoptotic caspases; BCL2; MOMP; immune checkpoint inhibition; senescence; type I interferon
    DOI:  https://doi.org/10.1080/2162402X.2024.2394247
  7. Life Sci Alliance. 2024 Nov;pii: e202402764. [Epub ahead of print]7(11):
    Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
    Vanessa Xavier, Silvia Martinelli, Ryan Corbyn, Rachel Pennie, Kai Rakovic, Ian R Powley, Leah Officer-Jones, Vincenzo Ruscica, Alison Galloway, Leo M Carlin, Victoria H Cowling, John Le Quesne, Jean-Claude Martinou, Thomas MacVicar.
      Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.
    DOI:  https://doi.org/10.26508/lsa.202402764
  8. Autophagy. 2024 Sep 03. 1-3
    Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.
    Hao Liu, Jianming Xie, Cien Zhen, Lin Zeng, Hualin Fan, Haixia Zhuang, Du Feng.
      Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.
    Keywords:  Autophagy; CGAS-STING1; LIR; TFAM; mitochondria DNA
    DOI:  https://doi.org/10.1080/15548627.2024.2395145
  9. FEBS Lett. 2024 Sep 03.
    Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
    Lishu Guo.
      The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
    Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition
    DOI:  https://doi.org/10.1002/1873-3468.15008
  10. J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746
    Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
    Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.
      Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
    Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1016/j.jbc.2024.107746
  11. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  12. Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952
    SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
    Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.
      Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
    Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)
    DOI:  https://doi.org/10.1016/j.mito.2024.101952
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