bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–07–02
nine papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Skeletal muscle, not adipose tissue, mediates cold-induced metabolic benefits.
  2. mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
  3. Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
  4. GDF15 promotes weight loss by enhancing energy expenditure in muscle.
  5. Molecular dynamics simulations reveal the hidden EF-hand of EF-SAM as a possible key thermal sensor for STIM1 activation by temperature.
  6. Proton transfer reactions: From photochemistry to biochemistry and bioenergetics.
  7. Biosynthesis and biotechnological production of the anti-obesity agent celastrol.
  8. Mechanisms of inward transmembrane proton translocation.
  9. Targeted cross-linker delivery for the in situ mapping of protein conformations and interactions in mitochondria.
  1. Nat Metab. 2023 Jun 26.
    Skeletal muscle, not adipose tissue, mediates cold-induced metabolic benefits.
    Logan K Townsend, Dongdong Wang, David C Wright, Denis P Blondin.
      
    DOI:  https://doi.org/10.1038/s42255-023-00837-4
  2. Nat Cell Biol. 2023 Jun 29.
    mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
    Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.
      Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.
    DOI:  https://doi.org/10.1038/s41556-023-01163-3
  3. EMBO J. 2023 Jun 28. e113687
    Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
    Gautier M Courbon, Paul R Palme, Lea Mann, Adrian Richter, Peter Imming, John L Rubinstein.
      Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
    Keywords:  ATP synthase; diarylquinoline; inhibitor; mycobacterial; squaramide
    DOI:  https://doi.org/10.15252/embj.2023113687
  4. Nature. 2023 Jun 28.
    GDF15 promotes weight loss by enhancing energy expenditure in muscle.
    Dongdong Wang, Logan K Townsend, Geneviève J DesOrmeaux, Sara M Frangos, Battsetseg Batchuluun, Lauralyne Dumont, Rune Ehrenreich Kuhre, Elham Ahmadi, Sumei Hu, Irena A Rebalka, Jaya Gautam, Maria Joy Therese Jabile, Chantal A Pileggi, Sonia Rehal, Eric M Desjardins, Evangelia E Tsakiridis, James S V Lally, Emma Sara Juracic, A Russell Tupling, Hertzel C Gerstein, Guillaume Paré, Theodoros Tsakiridis, Mary-Ellen Harper, Thomas J Hawke, John R Speakman, Denis P Blondin, Graham P Holloway, Sebastian Beck Jørgensen, Gregory R Steinberg.
      Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.
    DOI:  https://doi.org/10.1038/s41586-023-06249-4
  5. J Biol Chem. 2023 Jun 26. pii: S0021-9258(23)01998-1. [Epub ahead of print] 104970
    Molecular dynamics simulations reveal the hidden EF-hand of EF-SAM as a possible key thermal sensor for STIM1 activation by temperature.
    Andrei Neamtu, Dragomir N Serban, Greg J Barritt, Dragos Lucian Isac, Tudor Vasiliu, Aatto Laaksonen, Ionela Lacramioara Serban.
      Intracellular calcium signaling is essential for many cellular processes, including store-operated Ca2+ entry (SOCE), which is initiated by stromal interaction molecule 1 (STIM1) detecting endoplasmic reticulum (ER) Ca2+ depletion. STIM1 is also activated by temperature independently of ER Ca2+ depletion. Here we provide evidence, from advanced molecular dynamics simulations, that EF-SAM may act as a true temperature sensor for STIM1, with prompt and extended unfolding of the hidden EF-hand subdomain (hEF) even at slightly elevated temperatures, exposing a highly conserved hydrophobic Phe108. Our study also suggests an interplay between Ca2+ and temperature sensing, as both, the canonical EF-hand subdomain (cEF) and the hidden EF-hand subdomain (hEF), exhibit much higher thermal stability in the Ca2+-loaded form compared to the Ca2+-free form. The SAM domain, surprisingly, displays high thermal stability compared to the EF-hands, and may act as a stabilizer for the latter. We propose a modular architecture for the EF-hand-SAM domain of STIM1 composed of a thermal sensor (hEF), a Ca2+ sensor (cEF), and a stabilizing domain (SAM). Our findings provide important insights into the mechanism of temperature-dependent regulation of STIM1, which has broad implications for understanding the role of temperature in cellular physiology.
    Keywords:  calcium; calcium release-activated calcium channel protein 1 (Orai1); endoplasmic reticulum (ER); molecular dynamics; stromal interaction molecule 1 (STIM1)
    DOI:  https://doi.org/10.1016/j.jbc.2023.104970
  6. BBA Adv. 2023 ;3 100085
    Proton transfer reactions: From photochemistry to biochemistry and bioenergetics.
    Alexander P Demchenko.
      The present Review is an attempt by projecting the basic knowledge on photochemical proton transfer to achieve consistent understanding of proton motions in biocatalysis, photobiocatalysis, operation of selective proton channels and systems of photosynthesis and cellular respiration. The basic mechanisms of proton transfer are in active research in the electronic excited states of organic molecules. This allows observing the reactions directly in real time, providing their dynamic and thermodynamic description and coupling with structural and energetic variables. These achievements lay the background for understanding the proton transfers in biochemical reactions, where such ultrafast events are not only 'optically silent' but are hidden under much slower rate-limiting steps, such as protein conformational changes, substrate binding and product release. The mechanistic description of biocatalytic and transmembrane proton transport is shown as a multi-step proton migration that is available for modeling in photochemical reactions. For explaining the formation of transmembrane proton gradients, a simple 'proton lift' concept is presented that may be the basis of further research and analysis.
    Keywords:  Biochemical reactions of proton transfer; Light-activated reactions; Photosynthesis and cellular respiration; Proton channels; Proton transfer dynamics; Proton transfer photochemistry
    DOI:  https://doi.org/10.1016/j.bbadva.2023.100085
  7. Nat Chem. 2023 Jun 26.
    Biosynthesis and biotechnological production of the anti-obesity agent celastrol.
    Yong Zhao, Nikolaj L Hansen, Yao-Tao Duan, Meera Prasad, Mohammed S Motawia, Birger L Møller, Irini Pateraki, Dan Staerk, Søren Bak, Karel Miettinen, Sotirios C Kampranis.
      Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility. Here we elucidate the 11 missing steps for the celastrol biosynthetic route to enable its de novo biosynthesis in yeast. First, we reveal the cytochrome P450 enzymes that catalyse the four oxidation steps that produce the key intermediate celastrogenic acid. Subsequently, we show that non-enzymatic decarboxylation-triggered activation of celastrogenic acid leads to a cascade of tandem catechol oxidation-driven double-bond extension events that generate the characteristic quinone methide moiety of celastrol. Using this acquired knowledge, we have developed a method for producing celastrol starting from table sugar. This work highlights the effectiveness of combining plant biochemistry with metabolic engineering and chemistry for the scalable synthesis of complex specialized metabolites.
    DOI:  https://doi.org/10.1038/s41557-023-01245-7
  8. Nat Struct Mol Biol. 2023 Jun 29.
    Mechanisms of inward transmembrane proton translocation.
    Kirill Kovalev, Fedor Tsybrov, Alexey Alekseev, Vitaly Shevchenko, Dmytro Soloviov, Sergey Siletsky, Gleb Bourenkov, Michael Agthe, Marina Nikolova, David von Stetten, Roman Astashkin, Sergey Bukhdruker, Igor Chizhov, Antoine Royant, Alexander Kuzmin, Ivan Gushchin, Riccardo Rosselli, Francisco Rodriguez-Valera, Nikolay Ilyinskiy, Andrey Rogachev, Valentin Borshchevskiy, Thomas R Schneider, Ernst Bamberg, Valentin Gordeliy.
      Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have general universal features. However, elucidation of such mechanisms is a challenge. It requires true-atomic-resolution structures of all key proton-conducting states. Here we present a comprehensive function-structure study of a light-driven bacterial inward proton pump, xenorhodopsin, from Bacillus coahuilensis in all major proton-conducting states. The structures reveal that proton translocation is based on proton wires regulated by internal gates. The wires serve as both selectivity filters and translocation pathways for protons. The cumulative results suggest a general concept of proton translocation. We demonstrate the use of serial time-resolved crystallography at a synchrotron source with sub-millisecond resolution for rhodopsin studies, opening the door for principally new applications. The results might also be of interest for optogenetics since xenorhodopsins are the only alternative tools to fire neurons.
    DOI:  https://doi.org/10.1038/s41594-023-01020-9
  9. Nat Commun. 2023 Jun 30. 14(1): 3882
    Targeted cross-linker delivery for the in situ mapping of protein conformations and interactions in mitochondria.
    Yuwan Chen, Wen Zhou, Yufei Xia, Weijie Zhang, Qun Zhao, Xinwei Li, Hang Gao, Zhen Liang, Guanghui Ma, Kaiguang Yang, Lihua Zhang, Yukui Zhang.
      Current methods for intracellular protein analysis mostly require the separation of specific organelles or changes to the intracellular environment. However, the functions of proteins are determined by their native microenvironment as they usually form complexes with ions, nucleic acids, and other proteins. Here, we show a method for in situ cross-linking and analysis of mitochondrial proteins in living cells. By using the poly(lactic-co-glycolic acid) (PLGA) nanoparticles functionalized with dimethyldioctadecylammonium bromide (DDAB) to deliver protein cross-linkers into mitochondria, we subsequently analyze the cross-linked proteins using mass spectrometry. With this method, we identify a total of 74 pairs of protein-protein interactions that do not exist in the STRING database. Interestingly, our data on mitochondrial respiratory chain proteins ( ~ 94%) are also consistent with the experimental or predicted structural analysis of these proteins. Thus, we provide a promising technology platform for in situ defining protein analysis in cellular organelles under their native microenvironment.
    DOI:  https://doi.org/10.1038/s41467-023-39485-3
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