bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒09‒18
thirteen papers selected by
José Carlos de Lima-Júnior
University of California San Francisco
  1. A sensitive mitochondrial thermometry 2.0 and the availability of thermogenic capacity of brown adipocyte.
  2. Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats.
  3. Electric fields control water-gated proton transfer in cytochrome c oxidase.
  4. Altered skeletal muscle SERCA calcium transport efficiency following a thermogenic stimulus.
  5. A neurogenic signature involving monoamine oxidase-a controls human thermogenic adipose tissue development.
  6. No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial.
  7. Controlling transmembrane ion transport via photo-regulated carrier mobility.
  8. Nitric oxide derived from cytoglobin-deficient hepatic stellate cells causes suppression of cytochrome c oxidase activity in hepatocytes.
  9. Human cold habituation: Physiology, timeline, and modifiers.
  10. Housing-temperature reveals energy intake counter-balances energy expenditure in normal-weight, but not diet-induced obese, male mice.
  11. Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.
  12. Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
  13. Structure and mechanism of human cystine exporter cystinosin.
  1. Front Physiol. 2022 ;13 977431
    A sensitive mitochondrial thermometry 2.0 and the availability of thermogenic capacity of brown adipocyte.
    Xiao-Yan Meng, Dian-Dian Wang, Tao-Rong Xie, Run-Zhou Yang, Chun-Feng Liu, Dan-Hua Liu, Shu-Ang Li, Yi Luan, Jian-Sheng Kang.
      The temperature of a living cell is a crucial parameter for cellular events, such as cell division, gene expressions, enzyme activities and metabolism. We previously developed a quantifiable mitochondrial thermometry 1.0 based on rhodamine B methyl ester (RhB-ME) and rhodamine 800 (Rh800), and the theory for mitochondrial thermogenesis. Given that the synthesized RhB-ME is not readily available, thus, a convenient mitochondrial thermometry 2.0 based on tetra-methyl rhodamine methyl ester (TMRM) and Rh800 for the thermogenic study of brown adipocyte was further evolved. The fluorescence of TMRM is more sensitive (∼1.4 times) to temperature than that of RhB-ME, then the TMRM-based mito-thermometry 2.0 was validated and used for the qualitatively dynamic profiles for mitochondrial thermogenic responses and mitochondrial membrane potential in living cells simultaneously. Furthermore, our results demonstrated that the heterogenous thermogenesis evoked by β3 adrenoceptor agonist only used overall up to ∼46% of the thermogenic capacity evoked by CCCP stimulation. On the other hand, the results demonstrated that the maximum thermogenesis evoked by NE and oligomycin A used up to ∼79% of the thermogenic capacity, which suggested the maximum thermogenic capacity under physiological conditions by inhibiting the proton-ATPase function of the mitochondrial complex V, such as under the cold activation of sympathetic nerve and the co-release of sympathetic transmitters.
    Keywords:  Rh800; TMRM; brown adipocytes; mitochondrial thermometry 2.0; thermogenesis
    DOI:  https://doi.org/10.3389/fphys.2022.977431
  2. Lipids. 2022 Sep 13.
    Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats.
    Ana Paula Assis, Karine Emanuelle Silva, Natalia Lautherbach, Henrique Jorge Novaes Morgan, Maria Antonieta Rissato Garófalo, Neusa Maria Zanon, Luiz Carlos Carvalho Navegantes, Valéria Ernestânia Chaves, Isis do Carmo Kettelhut.
      Although it is well established that glucocorticoids inactivate thermogenesis and promote lipid accumulation in interscapular brown adipose tissue (IBAT), the underlying mechanisms remain unknown. We found that dexamethasone treatment (1 mg/kg) for 7 days in rats decreased the IBAT thermogenic activity, evidenced by its lower responsiveness to noradrenaline injection associated with reduced content of mitochondrial proteins, respiratory chain protein complexes, noradrenaline, and the β3 -adrenergic receptor. In parallel, to understand better how dexamethasone increases IBAT lipid content, we also investigated the activity of the ATP citrate lyase (ACL), a key enzyme of de novo fatty acid synthesis, glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, and the three glycerol-3-P generating pathways: (1) glycolysis, estimated by 2-deoxyglucose uptake, (2) glyceroneogenesis, evaluated by phosphoenolpyruvate carboxykinase activity and pyruvate incorporation into triacylglycerol-glycerol, and (3) direct phosphorylation of glycerol, investigated by the content and activity of glycerokinase. Dexamethasone increased the mass and the lipid content of IBAT as well as plasma levels of glucose, insulin, non-esterified fatty acid, and glycerol. Furthermore, dexamethasone increased ACL and G6PD activities (79% and 48%, respectively). Despite promoting a decrease in the incorporation of U-[14 C]-glycerol into triacylglycerol (~54%), dexamethasone increased the content (~55%) and activity (~41%) of glycerokinase without affecting glucose uptake or glyceroneogenesis. Our data suggest that glucocorticoid administration reduces IBAT thermogenesis through sympathetic inactivation and stimulates glycerokinase activity and content, contributing to increased generation of glycerol-3-P, which is mostly used to esterify fatty acid and increase triacylglycerol content promoting IBAT whitening.
    Keywords:  brown adipose tissue; glucocorticoids; glycerokinase; thermogenesis; triacylglycerol
    DOI:  https://doi.org/10.1002/lipd.12358
  3. Proc Natl Acad Sci U S A. 2022 Sep 20. 119(38): e2207761119
    Electric fields control water-gated proton transfer in cytochrome c oxidase.
    Patricia Saura, Daniel Riepl, Daniel M Frey, Mårten Wikström, Ville R I Kaila.
      Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme a, leads to dissociation of an arginine (Arg438)-heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å-1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, "chemical," proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.
    Keywords:  PCET; QM/MM; bioenergetics; heme-copper oxidases; molecular simulations
    DOI:  https://doi.org/10.1073/pnas.2207761119
  4. Am J Physiol Regul Integr Comp Physiol. 2022 Sep 12.
    Altered skeletal muscle SERCA calcium transport efficiency following a thermogenic stimulus.
    Lydia A Heemstra, Lauren G Koch, Steven L Britton, Colleen M Novak.
      Exposure to predator threat induces a rapid and robust increase in skeletal muscle thermogenesis in rats. The central nervous system relays threat information to skeletal muscle through activation of the sympathetic nervous system, but muscle mechanisms mediating this thermogenesis remain unidentified. Given the relevance of sarcolipin-mediated futile calcium cycling through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump to mammalian muscle non-shivering thermogenesis, we hypothesized that this plays a role in contextually induced muscle thermogenesis as well. This was assessed by measuring enzymatic activity of SERCA and sarcoplasmic reticulum Ca2+ transport, where the apparent coupling ratio-Ca2+ uptake rate divided by ATPase activity rate at a standard Ca2+ concentration-was predicted to decrease in association with muscle thermogenesis. Sprague Dawley rats exposed to predator (ferret) odor (PO) showed a rapid decrease in the apparent coupling ratio in the soleus muscle, indicating SERCA uncoupling compared to control-odor-exposed rats. A rat model of high aerobic fitness and elevated muscle thermogenesis also demonstrated soleus muscle SERCA uncoupling relative to their obesity-prone, low-fitness counterparts. Both the high- and low-aerobic fitness rats showed soleus SERCA uncoupling with exposure to PO. Lastly, no increase in sarcolipin expression in soleus muscle was detected with PO exposure. This dataset implicates muscle uncoupling of SERCA Ca2+ transport and ATP hydrolysis, likely through altered SERCA or sarcolipin function outside of translational regulation, as one contributor to the muscle thermogenesis provoked by exposure to predator threat. These data support the involvement of SERCA uncoupling in both muscle thermogenic induction and enhanced aerobic capacity.
    Keywords:  aerobic fitness; futile calcium cycling; high- and low-capacity runners; sarcolipin; uncoupling
    DOI:  https://doi.org/10.1152/ajpregu.00173.2022
  5. Elife. 2022 Sep 15. pii: e78945. [Epub ahead of print]11
    A neurogenic signature involving monoamine oxidase-a controls human thermogenic adipose tissue development.
    Javier Solivan-Rivera, Zinger Yang Loureiro, Tiffany DeSouza, Anand Desai, Sabine Pallat, Qin Yang, Raziel Rojas-Rodriguez, Rachel Ziegler, Pantos Skritakis, Shannon Joyce, Denise Zhong, Tammy Nguyen, Silvia Corvera.
      Mechanisms that control 'beige/brite' thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS4, TNC, NTRK3 and SPARCL1, which enhance neurogenesis, and decreased expression of MAOA and ACHE, which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.
    Keywords:  developmental biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.78945
  6. Nat Commun. 2022 Sep 12. 13(1): 5259
    No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial.
    Borja Martinez-Tellez, Guillermo Sanchez-Delgado, Francisco M Acosta, Juan M A Alcantara, Francisco J Amaro-Gahete, Wendy D Martinez-Avila, Elisa Merchan-Ramirez, Victoria Muñoz-Hernandez, Francisco J Osuna-Prieto, Lucas Jurado-Fasoli, Huiwen Xu, Lourdes Ortiz-Alvarez, María J Arias-Tellez, Andrea Mendez-Gutierrez, Idoia Labayen, Francisco B Ortega, Milena Schönke, Patrick C N Rensen, Concepción M Aguilera, José M Llamas-Elvira, Ángel Gil, Jonatan R Ruiz.
      Exercise modulates both brown adipose tissue (BAT) metabolism and white adipose tissue (WAT) browning in murine models. Whether this is true in humans, however, has remained unknown. An unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129) was therefore conducted to study the effects of a 24-week supervised exercise intervention, combining endurance and resistance training, on BAT volume and activity (primary outcome). The study was carried out in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada (Spain). One hundred and forty-five young sedentary adults were assigned to either (i) a control group (no exercise, n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 48), or (iii) a vigorous intensity exercise group (VIG-EX n = 43) by unrestricted randomization. No relevant adverse events were recorded. 97 participants (34 men, 63 women) were included in the final analysis (Control; n = 35, MOD-EX; n = 31, and VIG-EX; n = 31). We observed no changes in BAT volume (Δ Control: -22.2 ± 52.6 ml; Δ MOD-EX: -15.5 ± 62.1 ml, Δ VIG-EX: -6.8 ± 66.4 ml; P = 0.771) or 18F-fluorodeoxyglucose uptake (SUVpeak Δ Control: -2.6 ± 3.1 ml; Δ MOD-EX: -1.2 ± 4.8, Δ VIG-EX: -2.2 ± 5.1; p = 0.476) in either the control or the exercise groups. Thus, we did not find any evidence of an exercise-induced change on BAT volume or activity in young sedentary adults.
    DOI:  https://doi.org/10.1038/s41467-022-32502-x
  7. Chem Sci. 2022 Aug 24. 13(33): 9531-9536
    Controlling transmembrane ion transport via photo-regulated carrier mobility.
    Laura E Bickerton, Matthew J Langton.
      Stimuli-responsive transmembrane ion carriers allow for targeted and controllable transport activity, with potential applications as therapeutics for channelopathies and cancer, and in fundamental studies into ion transport phenomena. These applications require OFF-ON activation from a fully inactive state which does not exhibit background activity, but this remains challenging to achieve with synthetic transport systems. Here we introduce a novel mechanism for photo-gating mobile ion carriers, which involves modulating the mobility of the carriers within the lipid bilayer membrane. By appending a membrane-targeting anchor to the carrier using a photo-cleavable linker, the carrier's ion transport activity is fully switched off by suppressing its ability to shuttle between the two aqueous-membrane interfaces of the bilayer. The system can be reactivated rapidly in situ within the membrane by photo-triggered cleavage of the anchor to release the mobile ion carrier. This approach does not involve direct functionalization of the ion binding site of the carrier, and so does not require the de novo design of novel ion binding motifs to implement the photo-caging of activity. This work demonstrates that controlling the mobility of artificial transport systems enables precise control over activity, opening up new avenues for spatio-temporally targeted ionophores.
    DOI:  https://doi.org/10.1039/d2sc03322d
  8. Antioxid Redox Signal. 2022 Sep 16.
    Nitric oxide derived from cytoglobin-deficient hepatic stellate cells causes suppression of cytochrome c oxidase activity in hepatocytes.
    Yoshinori Okina, Misako Sato-Matsubara, Yasutoshi Kido, Hayato Urushima, Atsuko Daikoku, Chiho Kadono, Yu Nakagama, Yuko Nitahara, Truong Huu Hoang, Le Thi Thanh Thuy, Tsutomu Matsubara, Naoko Ohtani, Kazuo Ikeda, Katsutoshi Yoshizato, Norifumi Kawada.
      AIMS: Cell-cell interactions between hepatocytes and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes hepatocyte (Hep) dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of NO. Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression.RESULTS: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into neighboring hepatocytes to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. It's inhibitory action towards CcO specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo.
    INNOVATION AND CONCLUSION: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring hepatocyte dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO.
    DOI:  https://doi.org/10.1089/ars.2021.0279
  9. Temperature (Austin). 2022 ;9(2): 122-157
    Human cold habituation: Physiology, timeline, and modifiers.
    Beau R Yurkevicius, Billie K Alba, Afton D Seeley, John W Castellani.
      Habituation is an adaptation seen in many organisms, defined by a reduction in the response to repeated stimuli. Evolutionarily, habituation is thought to benefit the organism by allowing conservation of metabolic resources otherwise spent on sub-lethal provocations including repeated cold exposure. Hypermetabolic and/or insulative adaptations may occur after prolonged and severe cold exposures, resulting in enhanced cold defense mechanisms such as increased thermogenesis and peripheral vasoconstriction, respectively. Habituation occurs prior to these adaptations in response to short duration mild cold exposures, and, perhaps counterintuitively, elicits a reduction in cold defense mechanisms demonstrated through higher skin temperatures, attenuated shivering, and reduced cold sensations. These habituated responses likely serve to preserve peripheral tissue temperature and conserve energy during non-life threatening cold stress. The purpose of this review is to define habituation in general terms, present evidence for the response in non-human species, and provide an up-to-date, critical examination of past studies and the potential physiological mechanisms underlying human cold habituation. Our aim is to stimulate interest in this area of study and promote further experiments to understand this physiological adaptation.
    Keywords:  Adaptation; cold air exposure; cold shock response; cold water immersion; shivering; skin temperature; thermoregulation; vasoconstriction
    DOI:  https://doi.org/10.1080/23328940.2021.1903145
  10. Commun Biol. 2022 Sep 10. 5(1): 946
    Housing-temperature reveals energy intake counter-balances energy expenditure in normal-weight, but not diet-induced obese, male mice.
    Linu Mary John, Natalia Petersen, Marina Kjærgaard Gerstenberg, Lola Torz, Kent Pedersen, Berit Østergaard Christoffersen, Rune Ehrenreich Kuhre.
      Most metabolic studies on mice are performed at room temperature, although under these conditions mice, unlike humans, spend considerable energy to maintain core temperature. Here, we characterize the impact of housing temperature on energy expenditure (EE), energy homeostasis and plasma concentrations of appetite- and glucoregulatory hormones in normal-weight and diet-induced obese (DIO) C57BL/6J mice fed chow or 45% high-fat-diet, respectively. Mice were housed for 33 days at 22, 25, 27.5, and 30 °C in an indirect-calorimetry-system. We show that energy expenditure increases linearly from 30 °C towards 22 °C and is ~30% higher at 22 °C in both mouse models. In normal-weight mice, food intake counter-balances EE. In contrast, DIO mice do not reduce food intake when EE is lowered. By end of study, mice at 30 °C, therefore, had higher body weight, fat mass and plasma glycerol and triglycerides than mice at 22 °C. Dysregulated counterbalancing in DIO mice may result from increased pleasure-based eating.
    DOI:  https://doi.org/10.1038/s42003-022-03895-8
  11. FEBS Lett. 2022 Sep 16.
    Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo.
    Roberto Codella, Tiago C Alves, Douglas E Befroy, Cheol Soo Choi, Livio Luzi, Douglas L Rothman, Richard G Kibbey, Gerald I Shulman.
      Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS) and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2-13 C]acetate incorporation into muscle [4-13 C]- , [3-13 C]-glutamate and [4-13 C]-glutamine by high resolution 13 C/1 H MRS. Using this approach we found that overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation.
    Keywords:  magnetic resonance spectroscopy; mitochondrial efficiency; mitochondrial uncoupling; muscle energy metabolism
    DOI:  https://doi.org/10.1002/1873-3468.14494
  12. J Cell Biol. 2022 Nov 07. pii: e202201160. [Epub ahead of print]221(11):
    Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
    Rajarshi Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W Elonkirjo, Anu Suomalainen, Edward J Usherwood, Henry N Higgs.
      Mitochondrial damage represents a dramatic change in cellular homeostasis. One rapid response is perimitochondrial actin polymerization, termed acute damage-induced actin (ADA). The consequences of ADA are not understood. In this study, we show evidence suggesting that ADA is linked to rapid glycolytic activation upon mitochondrial damage in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes. ADA-inducing treatments include CCCP, antimycin, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157 inhibits both ADA and the glycolytic increase within 5 min, supporting ADA's role in glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, mitochondrial DNA depletion and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent perimitochondrial actin filaments similar to ADA. CK666 treatment causes rapid mitochondrial actin loss and a drop in ATP in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.
    DOI:  https://doi.org/10.1083/jcb.202201160
  13. Cell. 2022 Sep 09. pii: S0092-8674(22)01114-X. [Epub ahead of print]
    Structure and mechanism of human cystine exporter cystinosin.
    Xue Guo, Philip Schmiege, Tufa E Assafa, Rong Wang, Yan Xu, Linda Donnelly, Michael Fine, Xiaodan Ni, Jiansen Jiang, Glenn Millhauser, Liang Feng, Xiaochun Li.
      Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanism and capture the key conformational states of the transport cycle. Our structures, along with functional studies and double electron-electron resonance spectroscopic investigations, reveal the molecular basis for the transporter's conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy.
    Keywords:  DEER; Keywords; Ragulator-Rag complex; X-ray crystallography; cryo-EM; cystinosin; cystinosis; fast adaptation; lysosomal storage disease; lysosomal transporter; membrane protein dynamics
    DOI:  https://doi.org/10.1016/j.cell.2022.08.020
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