bims-resufa Biomed News
on Respiratory supercomplex factors
Issue of 2024–11–17
two papers selected by
Gavin McStay, Liverpool John Moores University
  1. Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide.
  2. The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.
  1. Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2412780121
    Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide.
    Terezia Kovalova, Sylwia Król, Ana P Gamiz-Hernandez, Dan Sjöstrand, Ville R I Kaila, Peter Brzezinski, Martin Högbom.
      Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex III2IV2 of Mycobacterium smegmatis, a close homolog of Mycobacterium tuberculosis supercomplex. We show that LPZS binds to the Qo cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.
    Keywords:  cryo-EM; drug target; molecular simulations; respiratory chain; tuberculosis
    DOI:  https://doi.org/10.1073/pnas.2412780121
  2. Front Cell Dev Biol. 2024 ;12 1464773
    The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.
    Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Sara Falvo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.
       Introduction: The contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes.
    Methods: We used CB1-/- and CB1+/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis.
    Results and discussion: In the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1-/- mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPRmt). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPRmt and UPRER pathways.
    Keywords:  cannabinoid receptor 1; homeostasis; mitochondrial quality control; mitochondrial unfolded protein response; oxidative stress; respiratory chain supercomplexes
    DOI:  https://doi.org/10.3389/fcell.2024.1464773
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