bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023‒06‒25
nineteen papers selected by
José Carlos de Lima-Júnior
Washington University
  1. Structural basis for the binding of DNP and purine nucleotides onto UCP1.
  2. Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.
  3. Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.
  4. Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis.
  5. Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.
  6. Using a Combination of Indirect Calorimetry, Infrared Thermography, and Blood Glucose Levels to Measure Brown Adipose Tissue Thermogenesis in Humans.
  7. The ancestral shape of the access proton path of mitochondrial ATP synthases revealed by a split subunit-a.
  8. Chilled, starved or frozen: Insect mitochondrial adaptations to overcome the cold.
  9. Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues.
  10. Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.
  11. Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange.
  12. Wnt signaling preserves progenitor cell multipotency during adipose tissue development.
  13. How murine models of human disease and immunity are influenced by housing temperature and mild thermal stress.
  14. Brown fat has a sweet tooth.
  15. Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation.
  16. ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice.
  17. Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
  18. The dynamics of agonist-β2-adrenergic receptor activation induced by binding of GDP-bound Gs protein.
  19. Structural basis of mitochondrial protein import by the TIM23 complex.
  1. Nature. 2023 Jun 19.
    Structural basis for the binding of DNP and purine nucleotides onto UCP1.
    Yunlu Kang, Lei Chen.
      Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat1,2. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP3-5. However, the mechanism by which UCP1 binds these ligands remains elusive. Here, we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state, and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with TM2 and TM6. ATP also binds inside the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5, and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.
    DOI:  https://doi.org/10.1038/s41586-023-06332-w
  2. Nat Commun. 2023 Jun 23. 14(1): 3746
    Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.
    Anna Park, Kwang-Eun Kim, Isaac Park, Sang Heon Lee, Kun-Young Park, Minkyo Jung, Xiaoxu Li, Maroun Bou Sleiman, Su Jeong Lee, Dae-Soo Kim, Jaehoon Kim, Dae-Sik Lim, Eui-Jeon Woo, Eun Woo Lee, Baek Soo Han, Kyoung-Jin Oh, Sang Chul Lee, Johan Auwerx, Ji Young Mun, Hyun-Woo Rhee, Won Kon Kim, Kwang-Hee Bae, Jae Myoung Suh.
      Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-39106-z
  3. Biochimie. 2023 Jun 17. pii: S0300-9084(23)00146-3. [Epub ahead of print]214(Pt B): 77-85
    Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain.
    Salvatore Nesci.
      Mitochondria produce heat as a result of an ineffective H+ cycling of mitochondria respiration across the inner mitochondrial membrane (IMM). This event present in all mitochondria, known as proton leak, can decrease protonmotive force (Δp) and restore mitochondrial respiration by partially uncoupling the substrate oxidation from the ADP phosphorylation. During impaired conditions of ATP generation with F1FO-ATPase, the Δp increases and IMM is hyperpolarized. In this bioenergetic state, the respiratory complexes support H+ transport until the membrane potential stops the H+ pump activity. Consequently, the electron transfer is stalled and the reduced form of electron carriers of the respiratory chain can generate O2∙¯ triggering the cascade of ROS formation and oxidative stress. The physiological function to attenuate the production of O2∙¯ by Δp dissipation can be attributed to the proton leak supported by the translocases of IMM.
    Keywords:  Electron transport chain; Mitochondria; Proton conductance; Proton leak; Proton-motive force; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.biochi.2023.06.008
  4. Nat Metab. 2023 Jun 19.
    Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis.
    Grace Park, John A Haley, Johnny Le, Su Myung Jung, Timothy P Fitzgibbons, Ekaterina D Korobkina, Huawei Li, Shelagh M Fluharty, Qingbo Chen, Jessica B Spinelli, Chinmay M Trivedi, Cholsoon Jang, David A Guertin.
      Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.
    DOI:  https://doi.org/10.1038/s42255-023-00825-8
  5. Nat Metab. 2023 Jun 19.
    Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.
    Nagendra P Palani, Carla Horvath, Pascal N Timshel, Pytrik Folkertsma, Alexander G B Grønning, Tora I Henriksen, Lone Peijs, Verena H Jensen, Wenfei Sun, Naja Z Jespersen, Christian Wolfrum, Tune H Pers, Søren Nielsen, Camilla Scheele.
      Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution. Based on an extracellular matrix and developmental gene signature, we name the structural branch of cells structural Wnt-regulated adipose tissue-resident (SWAT) cells. When stripped from adipogenic cells, SWAT cells display a multipotent phenotype by reverting towards progenitor state or differentiating into new adipogenic cells, dependent on media. Label transfer algorithms recapitulate the cell types in human adipose tissue datasets. In conclusion, we provide a differentiation map of human adipocytes and define the multipotent SWAT cell, providing a new perspective on adipose tissue regulation.
    DOI:  https://doi.org/10.1038/s42255-023-00820-z
  6. J Vis Exp. 2023 Jun 02.
    Using a Combination of Indirect Calorimetry, Infrared Thermography, and Blood Glucose Levels to Measure Brown Adipose Tissue Thermogenesis in Humans.
    Lachlan Van Schaik, Christine Kettle, Rod A Green, Helen R Irving, Joseph A Rathner.
      In mammals, brown adipose tissue (BAT) is activated rapidly in response to cold in order to maintain body temperature. Although BAT has been studied greatly in small animals, it is difficult to measure the activity of BAT in humans. Therefore, little is known about the heat-generating capacity and physiological significance of BAT in humans, including the degree to which components of the diet can activate BAT. This is due to the limitations in the currently most used method to assess the activation of BAT-radiolabeled glucose (fluorodeoxyglucose or 18FDG) measured by positron emission tomography-computerized tomography (PET-CT). This method is usually performed in fasted subjects, as feeding induces glucose uptake by the muscles, which can mask the glucose uptake into the BAT. This paper describes a detailed protocol for quantifying total-body human energy expenditure and substrate utilization from BAT thermogenesis by combining indirect calorimetry, infrared thermography, and blood glucose monitoring in carbohydrate-loaded adult males. To characterize the physiological significance of BAT, measures of the impact of BAT activity on human health are critical. We demonstrate a protocol to achieve this by combining carbohydrate loading and indirect calorimetry with measurements of supraclavicular changes in temperature. This novel approach will help to understand the physiology and pharmacology of BAT thermogenesis in humans.
    DOI:  https://doi.org/10.3791/64451
  7. Mol Biol Evol. 2023 Jun 20. pii: msad146. [Epub ahead of print]
    The ancestral shape of the access proton path of mitochondrial ATP synthases revealed by a split subunit-a.
    Jonathan E Wong, Alena Zíková, Ondřej Gahura.
      The passage of protons across membranes through F1Fo-ATP synthases spins their rotors and drives synthesis of ATP. While the principle of torque generation by proton transfer is known, the mechanisms and routes of proton access and release and their evolution are not fully understood. Here, we show that the entry site and path of protons in the lumenal half-channel of mitochondrial ATP synthases are largely defined by a short N-terminal α-helix of subunit-a. In Trypanosoma brucei and other Euglenozoa, the α-helix is part of another polypeptide chain that is a product of subunit-a gene fragmentation. This α-helix and other elements forming the proton pathway are widely conserved across eukaryotes and in Alphaproteobacteria, the closest extant relatives of mitochondria, but not in other bacteria. The α-helix blocks one of two proton routes found in Escherichia coli, resulting in the single proton entry site in mitochondrial and alphaproteobacterial ATP synthases. Thus, the shape of the access half-channel predates eukaryotes and originated in the lineage from which mitochondria evolved by endosymbiosis.
    DOI:  https://doi.org/10.1093/molbev/msad146
  8. Curr Opin Insect Sci. 2023 Jun 16. pii: S2214-5745(23)00073-1. [Epub ahead of print] 101076
    Chilled, starved or frozen: Insect mitochondrial adaptations to overcome the cold.
    Jacqueline E Lebenzon, Johannes Overgaard, Lisa Bjerregaard Jørgensen.
      Physiological adaptations to tackle cold exposure are crucial for insects living in temperate and arctic environments and here we review how cold adaptation is manifested in terms of mitochondrial function. Cold challenges are diverse, and different insect species have evolved metabolic and mitochondrial adaptations to: i) energize homeostatic regulation at low temperature, ii) stretch energy reserves during prolonged cold exposure, and iii) preserve structural organization of organelles following extracellular freezing. While the literature is still sparse, our review suggests that cold-adapted insects preserve ATP production at low temperatures by maintaining preferred mitochondrial substrate oxidation, which is otherwise challenged in cold-sensitive species. Chronic cold exposure and metabolic depression during dormancy is linked to reduced mitochondrial metabolism and may involve mitochondrial degradation. Finally, adaptation to extracellular freezing could be associated with superior structural integrity of the mitochondrial inner membrane following freezing which is linked to cellular and organismal survival.
    DOI:  https://doi.org/10.1016/j.cois.2023.101076
  9. Elife. 2023 Jun 23. pii: e85773. [Epub ahead of print]12
    Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues.
    Briana M Bohannon, Jessica J Jowais, Leif Nyberg, Vanessa Olivier-Meo, Valentina Corradi, D Peter Tieleman, Sara I Liin, H Peter Larsson.
      Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as Long QT Syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs-- channel - a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.
    Keywords:  molecular biophysics; structural biology; xenopus
    DOI:  https://doi.org/10.7554/eLife.85773
  10. bioRxiv. 2023 Jun 06. pii: 2023.06.06.543936. [Epub ahead of print]
    Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.
    Yung-Chi Tu, Fan-Yi Chao, Ming-Feng Tsai.
      The mitochondrial Ca 2+ uniporter mediates the crucial cellular process of mitochondrial Ca 2+ uptake, which regulates cell bioenergetics, intracellular Ca 2+ signaling, and cell death initiation. The uniporter contains the pore-forming MCU subunit, an EMRE protein that binds to MCU, and the regulatory MICU1 subunit, which can dimerize with MICU1 or MICU2 and under resting cellular [Ca 2+ ] occludes the MCU pore. It has been known for decades that spermine, which is ubiquitously present in animal cells, can enhance mitochondrial Ca 2+ uptake, but the underlying mechanisms remain unclear. Here, we show that spermine exerts dual modulatory effects on the uniporter. In physiological concentrations of spermine, it enhances uniporter activity by breaking the physical interactions between MCU and the MICU1-containing dimers to allow the uniporter to constitutively take up Ca 2+ even in low [Ca 2+ ] conditions. This potentiation effect does not require MICU2 or the EF-hand motifs in MICU1. When [spermine] rises to millimolar levels, it inhibits the uniporter by targeting the pore region in a MICU-independent manner. The MICU1-dependent spermine potentiation mechanism proposed here, along with our previous finding that cardiac mitochondria have very low MICU1, can explain the puzzling observation in the literature that mitochondria in the heart show no response to spermine.
    DOI:  https://doi.org/10.1101/2023.06.06.543936
  11. Elife. 2023 Jun 23. pii: RP87178. [Epub ahead of print]12
    Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange.
    David N Tippett, Colum Breen, Stephen J Butler, Marta Sawicka, Raimund Dutzler.
      Members of the SLC26 family constitute a conserved class of anion transport proteins, which encompasses uncoupled transporters with channel-like properties, coupled exchangers and motor proteins. Among the 10 functional paralogs in humans, several participate in the secretion of bicarbonate in exchange with chloride and thus play an important role in maintaining pH homeostasis. Previously, we have elucidated the structure of murine SLC26A9 and defined its function as an uncoupled chloride transporter (Walter et al., 2019). Here we have determined the structure of the closely related human transporter SLC26A6 and characterized it as a coupled exchanger of chloride with bicarbonate and presumably also oxalate. The structure defines an inward-facing conformation of the protein that generally resembles known structures of SLC26A9. The altered anion selectivity between both paralogs is a consequence of a remodeled ion binding site located in the center of a mobile unit of the membrane-inserted domain, which also accounts for differences in the coupling mechanism.
    Keywords:  SLC26 family; chloride bicarbonate exchange; cryo electron microscopy; human; ion transport; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.87178
  12. Nat Metab. 2023 Jun 19.
    Wnt signaling preserves progenitor cell multipotency during adipose tissue development.
    Zinger Yang Loureiro, Shannon Joyce, Tiffany DeSouza, Javier Solivan-Rivera, Anand Desai, Pantos Skritakis, Qin Yang, Rachel Ziegler, Denise Zhong, Tammy T Nguyen, Ormond A MacDougald, Silvia Corvera.
      Mesenchymal stem/progenitor cells are essential for tissue development and repair throughout life, but how they are maintained under chronic differentiation pressure is not known. Using single-cell transcriptomics of human progenitor cells we find that adipose differentiation stimuli elicit two cellular trajectories: one toward mature adipocytes and another toward a pool of non-differentiated cells that maintain progenitor characteristics. These cells are induced by transient Wnt pathway activation and express numerous extracellular matrix genes and are therefore named structural Wnt-regulated adipose tissue cells. We find that the genetic signature of structural Wnt-regulated adipose tissue cells is present in adult human adipose tissue and adipose tissue developed from human progenitor cells in mice. Our results suggest a mechanism whereby adipose differentiation occurs concurrently with the maintenance of a mesenchymal progenitor cell pool, ensuring tissue development, repair and appropriate metabolic control over the lifetime.
    DOI:  https://doi.org/10.1038/s42255-023-00813-y
  13. Temperature (Austin). 2023 ;10(2): 166-178
    How murine models of human disease and immunity are influenced by housing temperature and mild thermal stress.
    Caitlin M James, Scott H Olejniczak, Elizabeth A Repasky.
      At the direction of The Guide and Use of Laboratory Animals, rodents in laboratory facilities are housed at ambient temperatures between 20°C and 26°C, which fall below their thermoneutral zone (TNZ). TNZ is identified as a range of ambient temperatures that allow an organism to regulate body temperature without employing additional thermoregulatory processes (e.g. metabolic heat production driven by norepinephrine), thus leading to mild, chronic cold stress. For mice, this chronic cold stress leads to increased serum levels of the catecholamine norepinephrine, which has direct effects on various immune cells and several aspects of immunity and inflammation. Here, we review several studies that have revealed that ambient temperature significantly impacts outcomes in various murine models of human diseases, particularly those in which the immune system plays a major role in its pathogenesis. The impact of ambient temperature on experimental outcomes raises questions regarding the clinical relevance of some murine models of human disease, since studies examining rodents housed within thermoneutral ambient temperatures revealed that rodent disease pathology more closely resembled that of humans. Unlike laboratory rodents, humans can modify their surroundings accordingly - by adjusting their clothing, the thermostat, or their physical activity - to live within the appropriate TNZ, offering a possible explanation for why many studies using murine models of human disease conducted at thermoneutrality better represent patient outcomes. Thus, it is strongly recommended that ambient housing temperature in such studies be consistently and accurately reported and recognized as an important experimental variable.
    Keywords:  adaptive thermogenesis; ambient temperature; brown adipose tissue; cancer; cardiovascular disease; chronic stress; cold stress; immunity; inflammation; laboratory housing conditions; metabolism; murine models; nesting material; obesity; standard temperature; sympathetic nervous system; temperature; thermoneutral temperature; thermoneutral zone
    DOI:  https://doi.org/10.1080/23328940.2022.2093561
  14. Nat Metab. 2023 Jun 19.
    Brown fat has a sweet tooth.
    Imke L Lemmer, Alexander Bartelt.
      
    DOI:  https://doi.org/10.1038/s42255-023-00824-9
  15. Nat Commun. 2023 Jun 21. 14(1): 3683
    Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation.
    Michael F Fuss, Jan-Philip Wieferig, Robin A Corey, Yvonne Hellmich, Igor Tascón, Joana S Sousa, Phillip J Stansfeld, Janet Vonck, Inga Hänelt.
      Cyclic di-AMP is the only known essential second messenger in bacteria and archaea, regulating different proteins indispensable for numerous physiological processes. In particular, it controls various potassium and osmolyte transporters involved in osmoregulation. In Bacillus subtilis, the K+/H+ symporter KimA of the KUP family is inactivated by c-di-AMP. KimA sustains survival at potassium limitation at low external pH by mediating potassium ion uptake. However, at elevated intracellular K+ concentrations, further K+ accumulation would be toxic. In this study, we reveal the molecular basis of how c-di-AMP binding inhibits KimA. We report cryo-EM structures of KimA with bound c-di-AMP in detergent solution and reconstituted in amphipols. By combining structural data with functional assays and molecular dynamics simulations we reveal how c-di-AMP modulates transport. We show that an intracellular loop in the transmembrane domain interacts with c-di-AMP bound to the adjacent cytosolic domain. This reduces the mobility of transmembrane helices at the cytosolic side of the K+ binding site and therefore traps KimA in an inward-occluded conformation.
    DOI:  https://doi.org/10.1038/s41467-023-38944-1
  16. J Lipid Res. 2023 Jun 21. pii: S0022-2275(23)00078-0. [Epub ahead of print] 100405
    ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice.
    Mary E Seramur, Sandy Sink, Anderson O'Brien Cox, Cristina M Furdui, Chia-Chi Chuang Key.
      Alpha/beta hydrolase domain-containing protein 4 (ABHD4) catalyzes the deacylation of N-acyl phosphatidyl-ethanolamine (NAPE) and lyso-NAPE to produce glycerophospho-N-acyl ethanolamine (GP-NAE). Through a variety of metabolic enzymes, NAPE, lyso-NAPE, and GP-NAE are ultimately converted into NAE, a group of bioactive lipids that control many physiological processes including inflammation, cognition, food intake, and lipolysis (i.e., oleoylethanolamide or OEA). In a diet-induced obese mouse model, adipose tissue ABHD4 gene expression positively correlated with adiposity. However, it is unknown whether ABHD4 is a causal or a reactive gene to obesity. To fill this knowledge gap, we generated an ABHD4 knockout (KO) 3T3-L1 pre-adipocyte. During adipogenic stimulation, ABHD4 KO pre-adipocytes had increased adipogenesis and lipid accumulation, suggesting ABHD4 is responding to (a reactive gene), not contributing to (not a causal gene), adiposity and may serve as a mechanism for protecting against obesity. However, we did not observe any differences in adiposity and metabolic outcomes between whole body ABHD4 KO or adipocyte specific ABHD4 KO mice and their littermate control mice (both male and female) on chow or a high fat diet. This might be because we found that deletion of ABHD4 did not affect NAE such as OEA production, even though ABHD4 was highly expressed in adipose tissue and correlated with fasting adipose OEA levels and lipolysis. These data suggest that ABHD4 plays a role in adipocyte differentiation in vitro but not in adipose tissue lipid metabolism in mice despite nutrient overload, possibly due to compensation from other NAPE and NAE metabolic enzymes.
    Keywords:  ABHD4; Adipocyte; Alpha/beta hydrolase domain; Lipogenesis; Lipolysis; N-acyl ethanolamine; Obesity; Oleoylethanolamide
    DOI:  https://doi.org/10.1016/j.jlr.2023.100405
  17. Science. 2023 Jun 23. 380(6651): eadh9351
    Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
    Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.
      In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.
    DOI:  https://doi.org/10.1126/science.adh9351
  18. Nat Chem. 2023 Jun 22.
    The dynamics of agonist-β2-adrenergic receptor activation induced by binding of GDP-bound Gs protein.
    Amirhossein Mafi, Soo-Kyung Kim, William A Goddard.
      There is considerable uncertainty about the mechanism by which the β2-adrenergic receptor (β2AR) is activated. Here we use molecular metadynamics computations to predict the mechanism by which an agonist induces the activation of the β2AR and its cognate Gs protein. We found that binding agonist alone to the inactive β2AR does not break the ionic lock and hence does not drive the β2AR towards the activated conformation. However, we found that attaching the inactive Gs protein to the agonist-bound inactive β2AR (containing the ionic lock) leads to partial insertion of Gαs-α5 into the core of β2AR, which breaks the ionic lock, leading to activation of the Gs protein coupled to β2AR. Upon activation, the Gαs protein undergoes a remarkable opening of the GDP binding pocket, making the GDP available for exchange or release. Concomitantly, Gαs-α5 undergoes a remarkable expansion in the β2AR cytoplasmic region after the ionic lock is broken, inducing TM6 to displace outward by ~5 Å from TM3.
    DOI:  https://doi.org/10.1038/s41557-023-01238-6
  19. Nature. 2023 Jun 21.
    Structural basis of mitochondrial protein import by the TIM23 complex.
    Sue Im Sim, Yuanyuan Chen, Diane L Lynch, James C Gumbart, Eunyong Park.
      Mitochondria import nearly all of their approximately 1,000-2,000 constituent proteins from the cytosol across their double-membrane envelope1-5. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM23 complex, mediates import of presequence-containing proteins (preproteins) into the mitochondrial matrix and inner membrane. Among about ten different subunits of the TIM23 complex, the essential multipass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel6-11. However, the mechanism by which these subunits form a translocation path in the membrane and enable the import process remains unclear due to a lack of structural information. Here we determined the cryo-electron microscopy structure of the core TIM23 complex (heterotrimeric Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. Contrary to the prevailing model, Tim23 and Tim17 themselves do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Our structural and biochemical analyses show that the cavity of Tim17, but not Tim23, forms the protein translocation path, whereas Tim23 probably has a structural role. The results further suggest that, during translocation of substrate polypeptides, the nonessential subunit Mgr2 seals the lateral opening of the Tim17 cavity to facilitate the translocation process. We propose a new model for the TIM23-mediated protein import and sorting mechanism, a central pathway in mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s41586-023-06239-6
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