bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒06‒12
eleven papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization.
  2. Mechanism of mitoribosomal small subunit biogenesis and preinitiation.
  3. Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.
  4. GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
  5. Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
  6. PEX11β and FIS1 cooperate in peroxisome division independent of Mitochondrial Fission Factor.
  7. Mitochondria ROS and mitophagy in acute kidney injury.
  8. The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.
  9. Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
  10. Major construction entails major demolition.
  11. Mining the mitochondrial proteome.
  1. Cell. 2022 May 30. pii: S0092-8674(22)00590-6. [Epub ahead of print]
    Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization.
    Xuefeng Zhu, Xie Xie, Hrishikesh Das, Benedict G Tan, Yonghong Shi, Ali Al-Behadili, Bradley Peter, Elisa Motori, Sebastian Valenzuela, Viktor Posse, Claes M Gustafsson, B Martin Hällberg, Maria Falkenberg.
      The mitochondrial genome encodes 13 components of the oxidative phosphorylation system, and altered mitochondrial transcription drives various human pathologies. A polyadenylated, non-coding RNA molecule known as 7S RNA is transcribed from a region immediately downstream of the light strand promoter in mammalian cells, and its levels change rapidly in response to physiological conditions. Here, we report that 7S RNA has a regulatory function, as it controls levels of mitochondrial transcription both in vitro and in cultured human cells. Using cryo-EM, we show that POLRMT dimerization is induced by interactions with 7S RNA. The resulting POLRMT dimer interface sequesters domains necessary for promoter recognition and unwinding, thereby preventing transcription initiation. We propose that the non-coding 7S RNA molecule is a component of a negative feedback loop that regulates mitochondrial transcription in mammalian cells.
    Keywords:  7S RNA; POLRMT; SUV3; cryo-EM; dimer; mitochondria; mtDNA; mtEXO; non-coding RNA; transcription
    DOI:  https://doi.org/10.1016/j.cell.2022.05.006
  2. Nature. 2022 Jun 08.
    Mechanism of mitoribosomal small subunit biogenesis and preinitiation.
    Yuzuru Itoh, Anas Khawaja, Ivan Laptev, Miriam Cipullo, Ilian Atanassov, Petr Sergiev, Joanna Rorbach, Alexey Amunts.
      Mitoribosomes are essential for the synthesis and maintenance of bioenergetic proteins. Here we use cryo-electron microscopy to determine a series of the small mitoribosomal subunit (SSU) intermediates in complex with auxiliary factors, revealing a sequential assembly mechanism. The methyltransferase TFB1M binds to partially unfolded rRNA h45 that is promoted by RBFA, while the mRNA channel is blocked. This enables binding of METTL15 that promotes further rRNA maturation and a large conformational change of RBFA. The new conformation allows initiation factor mtIF3 to already occupy the subunit interface during the assembly. Finally, the mitochondria-specific ribosomal protein mS37 (ref. 1) outcompetes RBFA to complete the assembly with the SSU-mS37-mtIF3 complex2 that proceeds towards mtIF2 binding and translation initiation. Our results explain how the action of step-specific factors modulate the dynamic assembly of the SSU, and adaptation of a unique protein, mS37, links the assembly to initiation to establish the catalytic human mitoribosome.
    DOI:  https://doi.org/10.1038/s41586-022-04795-x
  3. Elife. 2022 Jun 08. pii: e75426. [Epub ahead of print]11
    Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.
    Holly C Ford, William J Allen, Gonçalo C Pereira, Xia Liu, Mark Simon Dillingham, Ian Collinson.
      Nearly all mitochondrial proteins need to be targeted for import from the cytosol. For the majority, the first port of call is the translocase of the outer membrane (TOM complex), followed by a procession of alternative molecular machines, conducting transport to their final destination. The pre-sequence translocase of the inner-membrane (TIM23-complex) imports proteins with cleavable pre-sequences. Progress in understanding these transport mechanisms has been hampered by the poor sensitivity and time-resolution of import assays. However, with the development of an assay based on split NanoLuc luciferase, we can now explore this process in greater detail. Here, we apply this new methodology to understand how ∆ψ and ATP hydrolysis, the two main driving forces for import into the matrix, contribute to the transport of pre-sequence-containing precursors (PCPs) with varying properties. Notably, we found that two major rate-limiting steps define PCP import time: passage of PCP across the outer membrane and initiation of inner membrane transport by the pre-sequence - the rates of which are influenced by PCP properties such as size and net charge. The apparent distinction between transport through the two membranes (passage through TOM is substantially complete before PCP-TIM engagement) is in contrast with the current view that import occurs through TOM and TIM in a single continuous step. Our results also indicate that PCPs spend very little time in the TIM23 channel - presumably rapid success or failure of import is critical for maintaining mitochondrial fitness.
    Keywords:  S. cerevisiae; biochemistry; chemical biology
    DOI:  https://doi.org/10.7554/eLife.75426
  4. Commun Biol. 2022 Jun 03. 5(1): 541
    GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
    Christina Wolf, Alireza Pouya, Sara Bitar, Annika Pfeiffer, Diones Bueno, Liliana Rojas-Charry, Sabine Arndt, David Gomez-Zepeda, Stefan Tenzer, Federica Dal Bello, Caterina Vianello, Sandra Ritz, Jonas Schwirz, Kristina Dobrindt, Michael Peitz, Eva-Maria Hanschmann, Pauline Mencke, Ibrahim Boussaad, Marion Silies, Oliver Brüstle, Marta Giacomello, Rejko Krüger, Axel Methner.
      Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.
    DOI:  https://doi.org/10.1038/s42003-022-03487-6
  5. Nat Cancer. 2022 Jun 09.
    Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
    Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.
      Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.
    DOI:  https://doi.org/10.1038/s43018-022-00393-y
  6. J Cell Sci. 2022 Jun 09. pii: jcs.259924. [Epub ahead of print]
    PEX11β and FIS1 cooperate in peroxisome division independent of Mitochondrial Fission Factor.
    Tina A Schrader, Ruth E Carmichael, Markus Islinger, Joseph L Costello, Christian Hacker, Nina A Bonekamp, Jochen H Weishaupt, Peter M Andersen, Michael Schrader.
      Peroxisome membrane dynamics and division are essential to adapt the peroxisomal compartment to cellular needs. The peroxisomal membrane protein PEX11β, and the tail-anchored adaptor proteins FIS1 (mitochondrial fission protein 1) and MFF (mitochondrial fission factor), which recruit the fission GTPase DRP1 (dynamin-related protein 1) to both peroxisomes and mitochondria, are key factors of peroxisomal division. The current model suggests MFF is essential for peroxisome division, whereas the role of FIS1 is unclear. Here, we reveal that PEX11β can promote peroxisome division in the absence of MFF in a DRP1- and FIS1-dependent manner. We also demonstrate that MFF permits peroxisome division independent of PEX11β and restores peroxisome morphology in PEX11β-deficient patient cells. Moreover, targeting of PEX11β to mitochondria induces mitochondrial division indicating the potential for PEX11β to modulate mitochondrial dynamics. Our findings suggest the existence of an alternative, MFF-independent pathway in peroxisome division and report a function for FIS1 in peroxisome division.
    Keywords:  FIS1; MFF; Mitochondria; Organelle division; PEX11; Peroxisomes
    DOI:  https://doi.org/10.1242/jcs.259924
  7. Autophagy. 2022 Jun 09. 1-14
    Mitochondria ROS and mitophagy in acute kidney injury.
    Lianjiu Su, Jiahao Zhang, Hernando Gomez, John A Kellum, Zhiyong Peng.
      Mitophagy is an essential mitochondrial quality control mechanism that eliminates damaged mitochondria and the production of reactive oxygen species (ROS). The relationship between mitochondria oxidative stress, ROS production and mitophagy are intimately interwoven, and these processes are all involved in various pathological conditions of acute kidney injury (AKI). The elimination of damaged mitochondria through mitophagy in mammals is a complicated process which involves several pathways. Furthermore, the interplay between mitophagy and different types of cell death, such as apoptosis, pyroptosis and ferroptosis in kidney injury is unclear. Here we will review recent advances in our understanding of the relationship between ROS and mitophagy, the different mitophagy pathways, the relationship between mitophagy and cell death, and the relevance of these processes in the pathogenesis of AKI.Abbreviations: AKI: acute kidney injury; AMBRA1: autophagy and beclin 1 regulator 1; ATP: adenosine triphosphate; BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BH3: BCL2 homology domain 3; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CASP1: caspase 1; CAT: catalase; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CI-AKI: contrast-induced acute kidney injury; CISD1: CDGSH iron sulfur domain 1; CL: cardiolipin; CNP: 2',3'-cyclic nucleotide 3'-phosphodiesterase; DNM1L/DRP1: dynamin 1 like; E3: enzyme 3; ETC: electron transport chain; FA: folic acid; FUNDC1: FUN14 domain containing 1; G3P: glycerol-3-phosphate; G6PD: glucose-6-phosphate dehydrogenase; GPX: glutathione peroxidase; GSH: glutathione; GSK3B: glycogen synthase kinase 3 beta; GSR: glutathione-disulfide reductase; HIF1A: hypoxia inducible factor 1 subunit alpha; HUWE1: HECT, UBA and WWE domain containing 1; IL1B: interleukin 1 beta; IMM: inner mitochondrial membrane; IPC: ischemic preconditioning; IRI: ischemia-reperfusion injury; LIR: LC3-interacting region; LPS: lipopolysaccharide; MA: malate-aspartate; MPT: mitochondrial permeability transition; MUL1: mitochondrial E3 ubiquitin protein ligase 1; mtROS: mitochondrial ROS; NLR: NOD-like receptor; NLRP3: NLR family pyrin domain containing 3; NOX: NADPH oxidase; OGD-R: oxygen-glucose deprivation-reperfusion; OMM: outer mitochondrial membrane; OPA1: OPA1 mitochondrial dynamin like GTPase; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PINK1: PTEN induced kinase 1; PLSCR3: phospholipid scramblase 3; PMP: peptidase, mitochondrial processing; PRDX: peroxiredoxin; PRKN: parkin RBR E3 ubiquitin protein ligase; RPTC: rat proximal tubular cells; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SOD: superoxide dismutase; SOR: superoxide reductase; SQSTM1/p62: sequestosome 1; TCA: tricarboxylic acid; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; TXN: thioredoxin; VDAC: voltage dependent anion channel; VCP: valosin containing protein.
    Keywords:  Acute kidney injury; cell death; mitochondria; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2022.2084862
  8. Autophagy. 2022 Jun 05. 1-2
    The retroviral restriction factor TRIM5/TRIM5α regulates mitochondrial quality control.
    Bhaskar Saha, Michael A Mandell.
      The protein TRIM5 is under intensive investigation related to its roles in antiviral defense, yet its underlying mechanisms of action remain elusive. In our study, we performed an unbiased identification of TRIM5-interacting partners and found proteins participating in a wide variety of cellular functions. We utilized this proteomics data set to uncover a role for TRIM5 in mitophagy, a mitochondrial quality control system that is impaired in multiple human diseases. Mitochondrial damage triggers the recruitment of TRIM5 to ER-mitochondria contact sites where TRIM5 colocalizes with markers of autophagosome biogenesis. Cells lacking TRIM5 are unable to carry out PRKN-dependent and PRKN-independent mitophagy pathways. TRIM5 knockout cells show reduced mitochondrial function and uncontrolled immune activation in response to mitochondrial damage; phenotypes consistent with a requirement for TRIM5 in mitophagy. Mechanistically, we found that TRIM5 is required for the recruitment of the autophagy initiation machinery to damaged mitochondria, where TRIM5 acts as a scaffold promoting interactions between protein markers of mitochondrial damage and the autophagy initiation machinery.
    Keywords:  APEX2; HIV-1; TRIM5α; autophagy; inflammation; mitochondria; mitophagy; restriction factor; tripartite-motif
    DOI:  https://doi.org/10.1080/15548627.2022.2084863
  9. EMBO Mol Med. 2022 Jun 07. e15851
    Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease.
    Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo.
      Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.
    Keywords:  Huntington's disease; heat shock transcription factor 1; human striatal organoids; mitochondrial DNA; single-stranded DNA-binding protein 1
    DOI:  https://doi.org/10.15252/emmm.202215851
  10. Dev Cell. 2022 Jun 06. pii: S1534-5807(22)00361-6. [Epub ahead of print]57(11): 1311-1313
    Major construction entails major demolition.
    Ekaterina Korotkevich, Takashi Hiiragi.
      Embryonic cells of the early mouse embryo become hypersensitive to apoptotic stimuli before gastrulation. In this issue of Developmental Cell, Pernaute et al. show that this switch in sensitivity is a result of a change in mitochondrial dynamics and mitophagy levels controlled by DRP1, a regulator of mitochondrial fission.
    DOI:  https://doi.org/10.1016/j.devcel.2022.05.008
  11. Nat Rev Mol Cell Biol. 2022 Jun 08.
    Mining the mitochondrial proteome.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-022-00503-9
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