bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–06–04
nine papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
  2. MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.
  3. Convergent molecular evolution of thermogenesis and circadian rhythm in Arctic ruminants.
  4. Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.
  5. Quantitative Determination of De Novo Fatty Acid Synthesis in Brown Adipose Tissue Using Deuterium Oxide.
  6. Ca2+ efflux facilitated by co-transport of inorganic phosphate anion in the H+/Ca2+ antiporter YfkE.
  7. Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels.
  8. Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae.
  9. A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.
  1. Sci Adv. 2023 Jun 02. 9(22): eadh4251
    Structural basis of purine nucleotide inhibition of human uncoupling protein 1.
    Scott A Jones, Prerana Gogoi, Jonathan J Ruprecht, Martin S King, Yang Lee, Thomas Zögg, Els Pardon, Deepak Chand, Stefan Steimle, Danielle M Copeman, Camila A Cotrim, Jan Steyaert, Paul G Crichton, Vera Moiseenkova-Bell, Edmund R S Kunji.
      Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo-electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier-like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak.
    DOI:  https://doi.org/10.1126/sciadv.adh4251
  2. Cell Chem Biol. 2023 May 22. pii: S2451-9456(23)00127-7. [Epub ahead of print]
    MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.
    Macarena Rodríguez-Prados, Kai-Ting Huang, Katalin Márta, Melanie Paillard, György Csordás, Suresh K Joseph, György Hajnóczky.
      Mitochondrial Ca2+ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca2+ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca2+-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharmacological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn2+-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU agonists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts.
    Keywords:  MCU; MICU1; Ru265; SB202190; calcium; kaempferol; ruthenium red; spermine
    DOI:  https://doi.org/10.1016/j.chembiol.2023.05.002
  3. Proc Biol Sci. 2023 May 31. 290(1999): 20230538
    Convergent molecular evolution of thermogenesis and circadian rhythm in Arctic ruminants.
    Manman Li, Xinmei Li, Zhipei Wu, Guanghui Zhang, Nini Wang, Mingle Dou, Shanlin Liu, Chentao Yang, Guanliang Meng, Hailu Sun, Christina Hvilsom, Guoxiang Xie, Yang Li, Zhuo Hui Li, Wei Wang, Yu Jiang, Rasmus Heller, Yu Wang.
      The muskox and reindeer are the only ruminants that have evolved to survive in harsh Arctic environments. However, the genetic basis of this Arctic adaptation remains largely unclear. Here, we compared a de novo assembled muskox genome with reindeer and other ruminant genomes to identify convergent amino acid substitutions, rapidly evolving genes and positively selected genes among the two Arctic ruminants. We found these candidate genes were mainly involved in brown adipose tissue (BAT) thermogenesis and circadian rhythm. Furthermore, by integrating transcriptomic data from goat adipose tissues (white and brown), we demonstrated that muskox and reindeer may have evolved modulating mitochondrion, lipid metabolism and angiogenesis pathways to enhance BAT thermogenesis. In addition, results from co-immunoprecipitation experiments prove that convergent amino acid substitution of the angiogenesis-related gene hypoxia-inducible factor 2alpha (HIF2A), resulting in weakening of its interaction with prolyl hydroxylase domain-containing protein 2 (PHD2), may increase angiogenesis of BAT. Altogether, our work provides new insights into the molecular mechanisms involved in Arctic adaptation.
    Keywords:  Arctic adaptation; brown adipose tissue; comparative genomics; convergent evolution; ruminant
    DOI:  https://doi.org/10.1098/rspb.2023.0538
  4. Nat Commun. 2023 Jun 02. 14(1): 3208
    Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging.
    Xu Feng, Liwen Wang, Ruoyu Zhou, Rui Zhou, Linyun Chen, Hui Peng, Yan Huang, Qi Guo, Xianghang Luo, Haiyan Zhou.
      Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-023-38842-6
  5. J Vis Exp. 2023 05 12.
    Quantitative Determination of De Novo Fatty Acid Synthesis in Brown Adipose Tissue Using Deuterium Oxide.
    Rory Turner, Rajib Mukherjee, Martina Wallace, Joan Sanchez-Gurmaches.
      Fatty acid synthesis is a complex and highly energy demanding metabolic pathway with important functional roles in the control of whole-body metabolic homeostasis and other physiological and pathological processes. Contrary to other key metabolic pathways, such as glucose disposal, fatty acid synthesis is not routinely functionally assessed, leading to incomplete interpretations of metabolic status. In addition, there is a lack of publicly available detailed protocols suitable for newcomers in the field. Here, we describe an inexpensive quantitative method utilizing deuterium oxide and gas chromatography mass spectrometry (GCMS) for the analysis of total fatty acid de novo synthesis in brown adipose tissue in vivo. This method measures the synthesis of the products of fatty acid synthase independently of a carbon source, and it is potentially useful for virtually any tissue, in any mouse model, and under any external perturbation. Details on the sample preparation for GCMS and downstream calculations are provided. We focus on the analysis of brown fat due to its high levels of de novo fatty acid synthesis and critical roles in maintaining metabolic homeostasis.
    DOI:  https://doi.org/10.3791/64219
  6. Commun Biol. 2023 May 29. 6(1): 573
    Ca2+ efflux facilitated by co-transport of inorganic phosphate anion in the H+/Ca2+ antiporter YfkE.
    Wei Niu, Wenchang Zhou, Shuo Lu, Trung Vu, Vasanthi Jayaraman, José D Faraldo-Gómez, Lei Zheng.
      Ca2+ is an important signaling messenger. In microorganisms, fungi, and plants, H+/Ca2+ antiporters (CAX) are known to play key roles in the homeostasis of intracellular Ca2+ by catalyzing its efflux across the cell membrane. Here, we reveal that the bacterial CAX homolog YfkE transports Ca2+ in two distinct modes: a low-flux H+/Ca2+ exchange mode and a high-flux mode in which Ca2+ and phosphate ions are co-transported (1:1) in exchange for H+. Coupling with phosphate greatly accelerates the Ca2+ efflux activity of YfkE. Our studies reveal that Ca2+ and phosphate bind to adjacent sites in a central translocation pathway and lead to mechanistic insights that explain how this CAX alters its conserved alpha-repeat motifs to adopt phosphate as a specific "transport chaperon" for Ca2+ translocation. This finding uncovers a co-transport mechanism within the CAX family that indicates this class of proteins contributes to the cellular homeostasis of both Ca2+ and phosphate.
    DOI:  https://doi.org/10.1038/s42003-023-04944-6
  7. Chem Biol Interact. 2023 May 25. pii: S0009-2797(23)00227-2. [Epub ahead of print]381 110560
    Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels.
    Plinio Bezerra Palácio, Geovanna Carvalho de Freitas Soares, Gabriella Moreira Bezerra Lima, Pedro Lourenzo Oliveira Cunha, Anna Lídia Nunes Varela, Heberty Tarso Facundo.
      Mitochondrial ATP-sensitive K+ channels (mitoKATP) have been recently characterized structurally, and possess a protein through which K+ enters mitochondria (MitoKIR), and a regulatory subunit (mitoSUR). The mitoSUR regulatory subunit is an ATP-binding cassette (ABC) protein isoform 8 (ABCB8). Opening these channels is known to be cardioprotective, but the molecular and physiological mechanisms that activate them are not fully known. Here, to better understand the molecular and physiological mechanisms of activators (GTP) and inhibitors (ATP) on the activity of mitoKATP, we exposed isolated mitochondria to both nucleotides. We also used molecular docking directed to the nucleotide-binding domain of human ABCB8/mitoSUR to test a comparative model of ATP and GTP effects. As expected, we find that ATP dose-dependently inhibits mitoKATP activity (IC50 = 21.24 ± 1.4 μM). However, simultaneous exposure of mitochondria to GTP dose-dependently (EC50 = 13.19 ± 1.33 μM) reversed ATP inhibition. Pharmacological and computational studies suggest that GTP reverses ATP activity competitively. Docking directed to the site of crystallized ADP reveals that both nucleotides bind to mitoSUR with high affinity, with their phosphates directed to the Mg2+ ion and the walker A motif of the protein (SGGGKTT). These effects, when combined, result in GTP binding, ATP displacement, mitochondrial ATP-sensitive K+ transport, and lower formation of reactive oxygen species. Overall, our findings demonstrate the basis for ATP and GTP binding in mitoSUR using a combination of biochemical, pharmacological, and computational experiments. Future studies may reveal the extent to which the balance between ATP and GTP actions contributes toward cardioprotection against ischemic events.
    Keywords:  ATP-Sensitive potassium channel; Free radicals; GTP; Mitochondria; Molecular docking
    DOI:  https://doi.org/10.1016/j.cbi.2023.110560
  8. Nat Commun. 2023 May 29. 14(1): 2542
    Structures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae.
    Fangzhu Han, Yiqi Hu, Mengchen Wu, Zhaoxiang He, Hongtao Tian, Long Zhou.
      Tetrahymena thermophila, a classic ciliate model organism, has been shown to possess tubular mitochondrial cristae and highly divergent electron transport chain involving four transmembrane protein complexes (I-IV). Here we report cryo-EM structures of its ~8 MDa megacomplex IV2 + (I + III2 + II)2, as well as a ~ 10.6 MDa megacomplex (IV2 + I + III2 + II)2 at lower resolution. In megacomplex IV2 + (I + III2 + II)2, each CIV2 protomer associates one copy of supercomplex I + III2 and one copy of CII, forming a half ring-shaped architecture that adapts to the membrane curvature of mitochondrial cristae. Megacomplex (IV2 + I + III2 + II)2 defines the relative position between neighbouring half rings and maintains the proximity between CIV2 and CIII2 cytochrome c binding sites. Our findings expand the current understanding of divergence in eukaryotic electron transport chain organization and how it is related to mitochondrial morphology.
    DOI:  https://doi.org/10.1038/s41467-023-38158-5
  9. Nat Metab. 2023 May;5(5): 861-879
    A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.
    Viktoria Glunk, Samantha Laber, Nasa Sinnott-Armstrong, Debora R Sobreira, Sophie M Strobel, Thiago M Batista, Phil Kubitz, Bahareh Nemati Moud, Hannah Ebert, Yi Huang, Beate Brandl, Garrett Garbo, Julius Honecker, David R Stirling, Nezar Abdennur, Virtu Calabuig-Navarro, Thomas Skurk, Soeren Ocvirk, Kerstin Stemmer, Beth A Cimini, Anne E Carpenter, Simon N Dankel, Cecilia M Lindgren, Hans Hauner, Marcelo A Nobrega, Melina Claussnitzer.
      Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00807-w
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