bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–02–11
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
  2. Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
  3. Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R.
  4. IL-4 activates futile triacylglyceride cycle for glucose utilization in white adipocytes.
  5. Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.
  6. Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.
  7. Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
  1. Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8
    Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
    Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.
      Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.
    Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
  2. FASEB J. 2024 Feb 15. 38(3): e23454
    Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
    Vitor M Ramos, Julian D C Serna, Eloisa A Vilas-Boas, João Victor Cabral-Costa, Fernanda M Cunha, Tetsushi Kataura, Viktor I Korolchuk, Alicia J Kowaltowski.
      Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.
    Keywords:  NCLX; autophagy regulation; calcium transport; caloric restriction; hepatocytes; mitochondria
    DOI:  https://doi.org/10.1096/fj.202301368RR
  3. Nat Commun. 2024 Feb 08. 15(1): 1192
    Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R.
    Camilla Lund, Pablo Ranea-Robles, Sarah Falk, Dylan M Rausch, Grethe Skovbjerg, Victoria Kamma Vibe-Petersen, Nathalie Krauth, Jacob Lercke Skytte, Vasiliki Vana, Urmas Roostalu, Tune H Pers, Jens Lund, Christoffer Clemmensen.
      Overfeeding triggers homeostatic compensatory mechanisms that counteract weight gain. Here, we show that both lean and diet-induced obese (DIO) male mice exhibit a potent and prolonged inhibition of voluntary food intake following overfeeding-induced weight gain. We reveal that FGF21 is dispensable for this defense against weight gain. Targeted proteomics unveiled novel circulating factors linked to overfeeding, including the protease  legumain (LGMN). Administration of recombinant LGMN lowers body weight and food intake in DIO mice. The protection against weight gain is also associated with reduced vascularization in the hypothalamus and sustained reductions in the expression of the orexigenic neuropeptide genes, Npy and Agrp, suggesting a role for hypothalamic signaling in this homeostatic recovery from overfeeding. Overfeeding of melanocortin 4 receptor (MC4R) KO mice shows that these mice can suppress voluntary food intake and counteract the enforced weight gain, although their rate of weight recovery is impaired. Collectively, these findings demonstrate that the defense against overfeeding-induced weight gain remains intact in obesity and involves mechanisms independent of both FGF21 and MC4R.
    DOI:  https://doi.org/10.1038/s41467-024-45223-0
  4. Biochem J. 2024 Feb 07. pii: BCJ20230486. [Epub ahead of print]
    IL-4 activates futile triacylglyceride cycle for glucose utilization in white adipocytes.
    Svetlana Michurina, Margarita Agareva, Ekaterina Zubkova, Mikhail Menshikov, Iurii Stafeev, Yelena Parfyonova.
      The development of cardiometabolic complications during obesity is strongly associated with chronic latent inflammation in hypertrophied adipose tissue (AT). IL-4 is an anti-inflammatory cytokine, playing a protective role against insulin resistance, glucose intolerance and weight gain. The positive effects of IL-4 are associated not only with the activation of anti-inflammatory immune cells in AT, but also with the modulation of adipocyte metabolism. IL-4 is known to activate lipolysis and glucose uptake in adipocytes, but the precise regulatory mechanisms and physiological significance of these processes remain unclear. In this study, we detail IL-4 effects on glucose and triacylglycerides (TAG) metabolism and propose mechanisms of IL-4 metabolic action in adipocytes.  We have shown that IL-4 activates glucose oxidation, lipid droplet (LD) fragmentation, lipolysis and thermogenesis in mature 3T3-L1 adipocytes. We found that lipolysis was not accompanied by fatty acids (FA) release from adipocytes, suggesting FA re-esterification. Moreover, glucose oxidation and thermogenesis stimulation depended on adipocyte triglyceride lipase (ATGL) activity, but not the uncoupling protein (UCP1) expression. Based on these data, IL-4 may activate the futile TAG-FA cycle in adipocytes, which enhances the oxidative activity of cells and heat production. Thus, the positive effect of IL-4 on systemic metabolism can be the result of activation of non-canonical thermogenic mechanism in AT, increasing TAG turnover and utilization of excessive glucose.
    Keywords:  Interleukin 4; TAG cycle; adipocytes; thermogenesis
    DOI:  https://doi.org/10.1042/BCJ20230486
  5. Nat Commun. 2024 Feb 05. 15(1): 1061
    Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain.
    Yao-Xu Mao, Zhi-Peng Chen, Liang Wang, Jie Wang, Cong-Zhao Zhou, Wen-Tao Hou, Yuxing Chen.
      Bilirubin is mainly generated from the breakdown of heme when red blood cells reach the end of their lifespan. Accumulation of bilirubin in human body usually leads to various disorders, including jaundice and liver disease. Bilirubin is conjugated in hepatocytes and excreted to bile duct via the ATP-binding cassette transporter ABCC2, dysfunction of which would lead to Dubin-Johnson syndrome. Here we determine the structures of ABCC2 in the apo, substrate-bound and ATP/ADP-bound forms using the cryo-electron microscopy, exhibiting a full transporter with a regulatory (R) domain inserted between the two half modules. Combined with substrate-stimulated ATPase and transport activity assays, structural analysis enables us to figure out transport cycle of ABCC2 with the R domain adopting various conformations. At the rest state, the R domain binding to the translocation cavity functions as an affinity filter that allows the substrates of high affinity to be transported in priority. Upon substrate binding, the R domain is expelled from the cavity and docks to the lateral of transmembrane domain following ATP hydrolysis. Our findings provide structural insights into a transport mechanism of ABC transporters finely tuned by the R domain.
    DOI:  https://doi.org/10.1038/s41467-024-45337-5
  6. Nature. 2024 Feb 07.
    Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.
    Feng He, Cheng-Guo Wu, Yang Gao, Sabrina N Rahman, Magda Zaoralová, Makaía M Papasergi-Scott, Ting-Jia Gu, Michael J Robertson, Alpay B Seven, Lingjun Li, Jesper M Mathiesen, Georgios Skiniotis.
      The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands.
    DOI:  https://doi.org/10.1038/s41586-024-07055-2
  7. FEBS Lett. 2024 Feb 04.
    Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
    Aksel J Saukko-Paavola, Robin W Klemm.
      Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.
    Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation
    DOI:  https://doi.org/10.1002/1873-3468.14813
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