bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022–11–27
ten papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Regulation of the mammalian-brain V-ATPase through ultraslow mode-switching.
  2. A proton-pumping enzyme in the brain switches between modes.
  3. SELECTIVE AND REVERSIBLE DISRUPTION OF MITOCHONDRIAL INNER MEMBRANE PROTEIN COMPLEXES BY LIPOPHILIC CATIONS.
  4. Role of bile acid receptor FXR in development and function of brown adipose tissue.
  5. Aqp5--/-- mice exhibit reduced maximal O2 consumption under cold exposure, normal pulmonary gas exchange, and impaired formation of brown adipose tissue.
  6. Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum.
  7. The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.
  8. SMP30-mediated synthesis of vitamin C activates the liver PPARα/FGF21 axis to regulate thermogenesis in mice.
  9. Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis.
  10. The longest-lived metazoan, Arctica islandica, exhibits high mitochondrial H2O2 removal capacities.
  1. Nature. 2022 Nov;611(7937): 827-834
    Regulation of the mammalian-brain V-ATPase through ultraslow mode-switching.
    Eleftherios Kosmidis, Christopher G Shuttle, Julia Preobraschenski, Marcelo Ganzella, Peter J Johnson, Salome Veshaguri, Jesper Holmkvist, Mads P Møller, Orestis Marantos, Frank Marcoline, Michael Grabe, Jesper L Pedersen, Reinhard Jahn, Dimitrios Stamou.
      Vacuolar-type adenosine triphosphatases (V-ATPases)1-3 are electrogenic rotary mechanoenzymes structurally related to F-type ATP synthases4,5. They hydrolyse ATP to establish electrochemical proton gradients for a plethora of cellular processes1,3. In neurons, the loading of all neurotransmitters into synaptic vesicles is energized by about one V-ATPase molecule per synaptic vesicle6,7. To shed light on this bona fide single-molecule biological process, we investigated electrogenic proton-pumping by single mammalian-brain V-ATPases in single synaptic vesicles. Here we show that V-ATPases do not pump continuously in time, as suggested by observing the rotation of bacterial homologues8 and assuming strict ATP-proton coupling. Instead, they stochastically switch between three ultralong-lived modes: proton-pumping, inactive and proton-leaky. Notably, direct observation of pumping revealed that physiologically relevant concentrations of ATP do not regulate the intrinsic pumping rate. ATP regulates V-ATPase activity through the switching probability of the proton-pumping mode. By contrast, electrochemical proton gradients regulate the pumping rate and the switching of the pumping and inactive modes. A direct consequence of mode-switching is all-or-none stochastic fluctuations in the electrochemical gradient of synaptic vesicles that would be expected to introduce stochasticity in proton-driven secondary active loading of neurotransmitters and may thus have important implications for neurotransmission. This work reveals and emphasizes the mechanistic and biological importance of ultraslow mode-switching.
    DOI:  https://doi.org/10.1038/s41586-022-05472-9
  2. Nature. 2022 Nov 23.
    A proton-pumping enzyme in the brain switches between modes.
      
    Keywords:  Biophysics; Cell biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-022-03617-4
  3. Mitochondrion. 2022 Nov 16. pii: S1567-7249(22)00103-9. [Epub ahead of print]
    SELECTIVE AND REVERSIBLE DISRUPTION OF MITOCHONDRIAL INNER MEMBRANE PROTEIN COMPLEXES BY LIPOPHILIC CATIONS.
    Anezka Kafkova, Lisa Tilokani, Filip Trčka, Veronika Šrámková, Marie Vancová, Tomáš Bílý, Jana Nebesařová, Julien Prudent, Jan Trnka.
      Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ.
    Keywords:  MitoQ; inner mitochondrial membrane; lipophilic cations; mitochondria; mitochondrial dynamics; respiratory chain
    DOI:  https://doi.org/10.1016/j.mito.2022.11.006
  4. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Nov 16. pii: S1388-1981(22)00147-0. [Epub ahead of print] 159257
    Role of bile acid receptor FXR in development and function of brown adipose tissue.
    J Yang, H D de Vries, A Mayeuf-Louchart, J H Stroeve, V W Bloks, M Koehorst, H Duez, B Staels, F Kuipers, T van Zutphen.
      Bile acids act as signalling molecules that contribute to maintenance of energy homeostasis in mice and humans. Activation of G-protein-coupled bile acid receptor TGR5 induces energy expenditure in brown adipose tissue (BAT). However, a role for the nuclear bile acid receptor Farnesoid X receptor (FXR) in BAT has remained ambiguous. We aimed to study the potential role of FXR in BAT development and functioning. Here we demonstrate low yet detectable expression of the α1/2 isoforms of FXR in murine BAT that markedly decreases upon cold exposure. Moderate adipose tissue-specific FXR overexpression in mice induces pronounced BAT whitening, presenting with large intracellular lipid droplets and extracellular collagen deposition. Expression of thermogenic marker genes including the target of Tgr5, Dio2, was significantly lower in BAT of chow-fed aP2-hFXR mice compared to wild-type controls. Transcriptomic analysis revealed marked up-regulation of extracellular matrix formation and down-regulation of mitochondrial functions in BAT from aP2-hFXR mice. In addition, markers of cell type lineages deriving from the dermomyotome, such as myocytes, as well as markers of cellular senescence were strongly induced. The response to cold and β3-adrenergic receptor agonism was blunted in these mice, yet resolved BAT whitening. Newborn cholestatic Cyp2c70-/- mice with a human-like bile acid profile also showed distinct BAT whitening and upregulation of myocyte-specific genes, while thermogenic markers were down-regulated. Ucp1 expression inversely correlated with plasma bile acid levels. Therefore, bile acid signalling via FXR has a role in BAT function already early in tissue development. Functionally, FXR activation appears to oppose TGR5-mediated thermogenesis.
    Keywords:  Bile acids; Brown adipose tissue; Cold exposure; Extracellular matrix; FXR; β3-Adrenergic receptor agonist
    DOI:  https://doi.org/10.1016/j.bbalip.2022.159257
  5. Am J Physiol Regul Integr Comp Physiol. 2022 Nov 21.
    Aqp5--/-- mice exhibit reduced maximal O2 consumption under cold exposure, normal pulmonary gas exchange, and impaired formation of brown adipose tissue.
    Samer Al-Samir, Ali Önder Yildirim, Venkataramana K Sidhaye, Landon S King, Gerhard Breves, Thomas M Conlon, Claudia Stoeger, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Gerolf Gros, Volker Endeward.
      The fundamental body functions that determine maximal O2 uptake (VO2,max) have not been studied in Aqp5 --/-- (aquaporin 5, AQP5) mice. We measured VO2,max to globally assess these functions and then investigated why it was found altered in Aqp5 --/-- mice. VO2,max was measured by the Helox technique, which elicits maximal metabolic rate by intense cold exposure of the animals. We found VO2,max reduced in Aqp5 --/-- mice by 20 - 30% compared to WT. Since AQP5 has been implicated to act as a membrane channel for respiratory gases, we studied whether this is due to the known lack of AQP5 in the alveolar epithelial membranes of Aqp5 --/-- mice. Lung function parameters as well as arterial O2 saturation were normal and identical between Aqp5 --/-- and WT mice, indicating that AQP5 does not contribute to pulmonary O2 exchange. The cause for the decreased VO2,max thus might be found in decreased O2 consumption of an intensely O2-consuming peripheral organ such as activated BAT. We found indeed that absence of AQP5 greatly reduces the amount of interscapular BAT formed in response to 4 weeks' cold exposure, from 63% in WT to 25% in Aqp5 --/-- animals. We conclude that lack of AQP5 does not affect pulmonary O2 exchange, but greatly inhibits transformation of white to brown adipose tissue. Since under cold exposure BAT is a major source of the animals' heat production, reduction of BAT likely causes the decrease in VO2,max under this condition.
    Keywords:  Aquaporin 5; alveolar-capillary barrier; gas channels; oxygen transport across membranes; pulmonary diffusion capacity
    DOI:  https://doi.org/10.1152/ajpregu.00130.2022
  6. Sci Adv. 2022 Nov 25. 8(47): eadc9952
    Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum.
    Eike Laube, Jakob Meier-Credo, Julian D Langer, Werner Kühlbrandt.
      Mitochondrial complex I is a redox-driven proton pump that generates proton-motive force across the inner mitochondrial membrane, powering oxidative phosphorylation and ATP synthesis in eukaryotes. We report the structure of complex I from the thermophilic fungus Chaetomium thermophilum, determined by cryoEM up to 2.4-Å resolution. We show that the complex undergoes a transition between two conformations, which we refer to as state 1 and state 2. The conformational switch is manifest in a twisting movement of the peripheral arm relative to the membrane arm, but most notably in substantial rearrangements of the Q-binding cavity and the E-channel, resulting in a continuous aqueous passage from the E-channel to subunit ND5 at the far end of the membrane arm. The conformational changes in the complex interior resemble those reported for mammalian complex I, suggesting a highly conserved, universal mechanism of coupling electron transport to proton pumping.
    DOI:  https://doi.org/10.1126/sciadv.adc9952
  7. Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2119824119
    The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.
    Eric M Desjardins, Brennan K Smith, Emily A Day, Serge Ducommun, Matthew J Sanders, Joshua P Nederveen, Rebecca J Ford, Stephen L Pinkosky, Logan K Townsend, Robert M Gutgesell, Rachel Lu, Kei Sakamoto, Gregory R Steinberg.
      Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.
    Keywords:  AMPK; NAFLD; autophagy; fat oxidation; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2119824119
  8. Exp Mol Med. 2022 Nov 25.
    SMP30-mediated synthesis of vitamin C activates the liver PPARα/FGF21 axis to regulate thermogenesis in mice.
    Bonggi Lee, Hye Jin An, Dae Hyun Kim, Min-Kyeong Lee, Hyeon Hak Jeong, Ki Wung Chung, Younghoon Go, Arnold Y Seo, Il Yong Kim, Je Kyung Seong, Byung Pal Yu, Jaewon Lee, Eunok Im, In-Kyu Lee, Myung-Shik Lee, Ken-Ichi Yamada, Hae Young Chung.
      The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.
    DOI:  https://doi.org/10.1038/s12276-022-00888-9
  9. Nat Commun. 2022 Nov 22. 13(1): 7162
    Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis.
    Mario Ruiz, Ranjan Devkota, Dimitra Panagaki, Per-Olof Bergh, Delaney Kaper, Marcus Henricsson, Ali Nik, Kasparas Petkevicius, Johanna L Höög, Mohammad Bohlooly-Y, Peter Carlsson, Jan Borén, Marc Pilon.
      Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using lipidomics and unbiased proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPARγ to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organisms achieve membrane homeostasis and adapt to a variable environment.
    DOI:  https://doi.org/10.1038/s41467-022-34931-0
  10. Mitochondrion. 2022 Nov 22. pii: S1567-7249(22)00102-7. [Epub ahead of print]
    The longest-lived metazoan, Arctica islandica, exhibits high mitochondrial H2O2 removal capacities.
    Daniel Munro, Enrique Rodríguez, Pierre U Blier.
      A greater capacity of endogenous matrix antioxidants has recently been hypothesized to characterize mitochondria of long-lived species, curbing bursts of reactive oxygen species (ROS) generated in this organelle. Evidence for this has been obtained from studies comparing the long-lived naked mole rat to laboratory mice. We tested this hypothesis by comparing the longest-lived metazoan, the marine bivalve Arctica islandica (MLSP=507 y), with shorter-lived and evolutionarily related species. We used a recently developed fluorescent technique to assess mantle and gill tissue mitochondria's capacity to consume hydrogen peroxide (H2O2) in multiple physiological states ex vivo. Depending on the type of respiratory substrate provided, mitochondria of Arctica islandica could consume between 3-14 times more H2O2 than shorter-lived species. These findings support the contention that a greater capacity for the elimination of ROS characterizes long-lived species, a novel property of mitochondria thus far demonstrated in two key biogerontological models from distant evolutionary lineages.
    Keywords:  Arctica islandica; bivalves; hydrogen peroxide; longevity; mitochondria; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.mito.2022.11.005
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