bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–08–25
twelve papers selected by
José Carlos de Lima-Júnior, Washington University
  1. A safety guide for transgenic Cre drivers in metabolism.
  2. Decoding temporal thermogenesis: coregulator selectivity and transcriptional control in brown and beige adipocytes.
  3. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  4. Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
  5. Inner membrane turns inside out to exit mitochondrial organelles.
  6. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  7. Iron supplementation and iron accumulation promote adipocyte thermogenesis through PGC1α-ATGL-mediated lipolysis.
  8. Association between thermogenic brown fat and genes under positive natural selection in circumpolar populations.
  9. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  10. The role of brown adipose tissue in branched-chain amino acid clearance in people.
  11. Mitochondrial uncoupling caused by a wide variety of protonophores is differently sensitive to carboxyatractyloside in rat heart and liver mitochondria.
  12. The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
  1. Nat Metab. 2024 Aug 19.
    A safety guide for transgenic Cre drivers in metabolism.
    Carla Horvath, Christian Wolfrum, Pawel Pelczar.
      
    DOI:  https://doi.org/10.1038/s42255-024-01087-8
  2. Adipocyte. 2024 Dec;13(1): 2391511
    Decoding temporal thermogenesis: coregulator selectivity and transcriptional control in brown and beige adipocytes.
    Yong Geun Jeon, Sun Won Kim, Jae Bum Kim.
      In mammals, brown adipose tissue (BAT) and beige adipocytes in white adipose tissue (WAT) play pivotal roles in maintaining body temperature and energy metabolism. In mice, BAT quickly stimulates thermogenesis by activating brown adipocytes upon cold exposure. In the presence of chronic cold stimuli, beige adipocytes are recruited in inguinal WAT to support heat generation. Accumulated evidence has shown that thermogenic execution of brown and beige adipocytes is regulated in a fat depot-specific manner. Recently, we have demonstrated that ubiquitin ligase ring finger protein 20 (RNF20) regulates brown and beige adipocyte thermogenesis through fat-depot-specific modulation. In BAT, RNF20 regulates transcription factor GA-binding protein alpha (GABPα), whereas in inguinal WAT, RNF20 potentiates transcriptional activity of peroxisome proliferator-activated receptor-gamma (PPARγ) through the degradation of nuclear corepressor 1 (NCoR1). This study proposes the molecular mechanisms by which co-regulator(s) selectively and temporally control transcription factors to coordinate adipose thermogenesis in a fat-depot-specific manner. In this Commentary, we provide molecular features of brown and beige adipocyte thermogenesis and discuss the underlying mechanisms of distinct thermogenic processes in two fat depots.
    Keywords:  RNF20; Thermogenesis; beige adipocyte; brown adipocyte; co-regulators
    DOI:  https://doi.org/10.1080/21623945.2024.2391511
  3. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  4. Nat Commun. 2024 Aug 22. 15(1): 7215
    Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue.
    Chih-Hao Wang, Tadataka Tsuji, Li-Hong Wu, Cheng-Ying Yang, Tian Lian Huang, Mari Sato, Farnaz Shamsi, Yu-Hua Tseng.
      Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-51579-0
  5. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  6. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  7. J Biol Chem. 2024 Aug 17. pii: S0021-9258(24)02191-4. [Epub ahead of print] 107690
    Iron supplementation and iron accumulation promote adipocyte thermogenesis through PGC1α-ATGL-mediated lipolysis.
    Xudong Mai, Yifan Liu, Jigang Fan, Lanling Xiao, Miaomiao Liao, Zhipeng Huang, Zijian Chen, Shaojun Huang, Rui Sun, Xiaowan Jiang, Liujing Huang, Jia Sun, Liwei Xie, Hong Chen.
      Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both Mitochondrial biogenesis and mitochondrial function are iron dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g. Tfr1, Hfe) are involved in cold induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe-/-) deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and ATGL, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction (SVF) from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe-/- mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or SVFs from WT mice supplemented with iron citrate (FAC) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues.
    Keywords:  Adipose thermogenesis; HFE; Iron homeostasis; Stromal vascular fractions
    DOI:  https://doi.org/10.1016/j.jbc.2024.107690
  8. J Physiol Anthropol. 2024 Aug 19. 43(1): 19
    Association between thermogenic brown fat and genes under positive natural selection in circumpolar populations.
    Yuka Ishida, Mami Matsushita, Takeshi Yoneshiro, Masayuki Saito, Kazuhiro Nakayama.
       BACKGROUND: Adaptation to cold was essential for human migration across Eurasia. Non-shivering thermogenesis through brown adipose tissue (BAT) participates in cold adaptation because some genes involved in the differentiation and function of BAT exhibit signatures of positive natural selection in populations at high latitudes. Whether these genes are associated with the inter-individual variability in BAT thermogenesis remains unclear. In this study, we evaluated the potential associations between BAT activity and single nucleotide polymorphisms (SNPs) in candidate gene regions in East Asian populations.
    METHODS: BAT activity induced by mild cold exposure was measured in 399 healthy Japanese men and women using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). The capacity for cold-induced thermogenesis and fat oxidation was measured in 56 men. Association analyses with physiological traits were performed for 11 SNPs at six loci (LEPR, ANGPTL8, PLA2G2A, PLIN1, TBX15-WARS2, and FADS1) reported to be under positive natural selection. Associations found in the FDG-PET/CT population were further validated in 84 healthy East Asian men and women, in whom BAT activity was measured using infrared thermography. Associations between the SNP genotypes and BAT activity or other related traits were tested using multiple logistic and linear regression models.
    RESULTS: Of the 11 putative adaptive alleles of the six genes, two intronic SNPs in LEPR (rs1022981 and rs12405556) tended to be associated with higher BAT activity. However, these did not survive multiple test comparisons. Associations with lower body fat percentage, plasma triglyceride, insulin, and HOMA-IR levels were observed in the FDG-PET/CT population (P < 0.05). Other loci, including TBX15-WARS2, which is speculated to mediate cold adaptation in Greenland Inuits, did not show significant differences in BAT thermogenesis.
    CONCLUSIONS: Our results suggest a marginal but significant association between LEPR SNPs. However, robust supporting evidence was not established for the involvement of other loci under positive natural selection in cold adaptation through BAT thermogenesis in East Asian adults. Given the pleiotropic function of these genes, factors other than cold adaptation through BAT thermogenesis, such as diet adaptation, may contribute to positive natural selection at these loci.
    Keywords:  Brown adipose tissue; Cold adaptation; Metabolism; Positive natural selection; Single nucleotide polymorphism
    DOI:  https://doi.org/10.1186/s40101-024-00368-1
  9. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  10. iScience. 2024 Aug 16. 27(8): 110559
    The role of brown adipose tissue in branched-chain amino acid clearance in people.
    Yasser G Abdelhafez, Guobao Wang, Siqi Li, Vanessa Pellegrinelli, Abhijit J Chaudhari, Anthony Ramirez, Fatma Sen, Antonio Vidal-Puig, Labros S Sidossis, Samuel Klein, Ramsey D Badawi, Maria Chondronikola.
      Brown adipose tissue (BAT) in rodents appears to be an important tissue for the clearance of plasma branched-chain amino acids (BCAAs) contributing to improved metabolic health. However, the role of human BAT in plasma BCAA clearance is poorly understood. Here, we evaluate patients with prostate cancer who underwent positron emission tomography-computed tomography imaging after an injection of 18F-fluciclovine (L-leucine analog). Supraclavicular adipose tissue (AT; primary location of human BAT) has a higher net uptake rate for 18F-fluciclovine compared to subcutaneous abdominal and upper chest AT. Supraclavicular AT 18F-fluciclovine net uptake rate is lower in patients with obesity and type 2 diabetes. Finally, the expression of genes involved in BCAA catabolism is higher in the supraclavicular AT of healthy people with high BAT volume compared to those with low BAT volume. These findings support the notion that BAT can potentially function as a metabolic sink for plasma BCAA clearance in people.
    Keywords:  Cancer; Human genetics; Human metabolism
    DOI:  https://doi.org/10.1016/j.isci.2024.110559
  11. Biochim Biophys Acta Bioenerg. 2024 Aug 20. pii: S0005-2728(24)00476-6. [Epub ahead of print]1865(4): 149506
    Mitochondrial uncoupling caused by a wide variety of protonophores is differently sensitive to carboxyatractyloside in rat heart and liver mitochondria.
    Ljudmila S Khailova, Roman S Kirsanov, Tatyana I Rokitskaya, Vladimir S Krasnov, Galina A Korshunova, Elena A Kotova, Yuri N Antonenko.
      Mitochondrial uncoupling by small-molecule protonophores is generally accepted to proceed via transmembrane proton shuttling. The idea of facilitating this process by the adenine nucleotide translocase ANT originated primarily from the partial reversal of the DNP-induced mitochondrial uncoupling by the ANT inhibitor carboxyatractyloside (CATR). Recently, the sensitivity to CATR was also observed for the action of such potent OxPhos uncouplers as BAM15, SF6847, FCCP and niclosamide. Here, we report measurements of the CATR effect on the activity of a large number of conventional and novel uncouplers in isolated mammalian mitochondria. Despite the broad variety of chemical structures, CATR attenuated the uncoupling efficacy of all the anionic protonophores in rat heart mitochondria with high abundance of ANT, whereas the effect was much less pronounced or even absent, e.g. for SF6847, in rat liver mitochondria with low ANT content. The fact that the uncoupling action is tissue specific for a broad spectrum of anionic protonophores is highlighted here for the first time. Only with the cationic uncoupler ellipticine and the channel-forming peptide gramicidin A, no sensitivity to CATR was found even in rat heart mitochondria. By contrast, with the recently described ester-stabilized ylidic protonophores [Kirsanov et al. Bioelectrochemistry 2023], the stimulating effect of CATR was discovered both in liver and heart mitochondria.
    Keywords:  Adenine nucleotide translocator; Carboxyatractyloside; Membrane potential; Mitochondrial uncoupler; Protonophore; Respiration rate
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149506
  12. Nat Commun. 2024 Aug 21. 15(1): 7121
    The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
    Marta Llovera, Leonor Gouveia, Antonio Zorzano, Daniel Sanchis.
      
    DOI:  https://doi.org/10.1038/s41467-024-51447-x
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