bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023‒02‒12
ten papers selected by
José Carlos de Lima-Júnior
Washington University

  1. J Am Chem Soc. 2023 Feb 06.
      Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.
  2. Eur J Nucl Med Mol Imaging. 2023 Feb 11.
      PURPOSE: Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown.METHODS AND RESULTS: In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation.
    CONCLUSION: These findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity.
    TRIAL REGISTRATION: EudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017.
    Keywords:  Inhibition; Neurometabolic coupling; PET; Satiation; Secretin; fMRI
  3. Life Sci. 2023 Feb 08. pii: S0024-3205(23)00127-3. [Epub ahead of print] 121493
      T cell activation process is critically affected by temperature and intracellular Ca2+-signalling. Yet, the nature and the key molecules involved in such complex Ca2+-signalling is poorly understood. It is mostly assumed that ion channels present in the plasma membrane primarily regulate the cytosolic Ca2+-levels exclusively. TRPV4 is a non-selective Ca2+ channel which can be activated at physiological temperature. TRPV4 is involved in several physiological, pathophysiological process as well as different forms of pain. Here we demonstrate that TRPV4 is endogenously expressed in T cell and is present in the mitochondria of T cells. TRPV4 activation increases mitochondrial Ca2+-levels, and alters mitochondrial temperature as well as specific metabolisms. The TRPV4-dependent increment in the mitochondrial Ca2+ is context-dependent and not just passively due to the increment in the cytosolic Ca2+. Our work also indicates that mitochondrial Ca2+-level correlates positively with a series of essential factors, such as mitochondrial membrane potential, mitochondrial ATP production and negatively correlates with certain factors such as mitochondrial temperature. We propose that TRPV4-mediated mitochondrial Ca2+-signalling and other metabolisms has implications in the immune activation process including immune synapse formation. Our data also endorse the re-evaluation of Ca2+-signalling in T cell, especially in the light of mitochondrial Ca2+-buffering and in higher body temperature, such as in case of fever. Presence of TRPV4 in the mitochondria of T cell is relevant for proper and optimum immune response and may provide evolutionary adaptive benefit. These findings may also have broad implications in different pathophysiological process, neuro-immune cross-talks, and channelopathies involving TRPV4.
    Keywords:  ATP; Ca2+; Cardiolipin; ER-mito contact sites; Membrane potential; Mitochondria; Pain; T cell; TCR activation; TRPV4; Temperature
  4. Comp Biochem Physiol B Biochem Mol Biol. 2023 Feb 04. pii: S1096-4959(23)00009-X. [Epub ahead of print]265 110834
      The purpose of this study was to investigate whether there is an interacting effect of six weeks of swimming in cold water on the gene expression of browning markers in adipose tissue in rodents. Twenty male Wistar rats were randomly divided into four groups: Control (C, 25 °C), Cold Exposure (CE, 4 °C), Swimming in tepid Water (STW, 30 °C), and Swimming in Cold Water (SCW, 15 °C). The swimming included 2-3 min intervals, 1 min rest, until exhaustion, three days a week for six weeks, with 3 to 6% of bodyweight overload. Rats from CE were exposed to cold for 2 h per day, five days per week. After the experimental protocol, interscapular brown (BAT) and inguinal subcutaneous white (WAT) fat tissues were excised, weighed, and processed for beiging and mitochondrial biogenesis markers gene expression. The experimental protocols resulted in an apparent increase in the number of brown adipocytes (per mm2) in the adipose deposits compared to the C group; substantial changes were observed in the SCW group. Compared to other groups, cold exposure alone increased significantly serum norepinephrine, and also β2-adrenergic receptor expression was upregulated in the adipocytes compared to the C group. The STW group increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1 alpha (PGC-1α), β2-adrenergic receptor, and CCAAT/enhancer-binding proteins-α(c/EBP-α) in WAT in comparison with the C group(p < 0.05). In both adipocytes, the SCW intervention significantly upregulated the expression of PGC-1α, PPAR-γ, and c/EBP-α genes in comparison with the C and CE groups. In addition, the expression of TFAM and UCP1 was upregulated substantially in the SCW group compared to other groups. Our data demonstrate that swim training and cold exposure present additive effects in the expression of genes involved in the beiging process and mitochondrial biogenesis markers in BAT and WAT. In addition, it seems that the upregulation of these genes is related to the activation of β2-adrenergic receptors.
    Keywords:  Brown fat tissue; Browning; Cold stress; Exercise training; Lose weight; White fat tissue
  5. Eur J Endocrinol. 2023 Feb 08. pii: lvad014. [Epub ahead of print]
      BACKGROUND: Adipose tissue plays a pivotal role in pathology of metabolic disorders. In the past decade brown and brown-like adipose tissue were detected in adult human and show therapeutic potential in aging-related metabolic diseases.OBJECTIVE: This study investigated expressions of major brown adipose markers in white adipose tissue of different ages. Their associations with metabolic parameters and key adipokines were interrogated.
    DESIGN: Cross-sectional study, 2019-2021.
    METHODS: We recruited 21 young, 67 middle-aged and 34 older patients. Omental adipose tissues were collected and expressions of key brown markers and adipokines, and adipocyte size were evaluated. The fat depot distribution was evaluated by computed tomography.
    RESULTS: UCP1 and PRDM16 mRNA expression declined with aging in WAT and were more associated with age, than with BMI. Increased VAT (visceral adipose tissue) amount, as well as VAT to subcutaneous adipose tissue (SAT) ratio, was decreased in the highest tertile of UCP1 expression, while individuals in different PRDM16 mRNA tertiles exhibited similar fat distribution. UCP1 mRNA was positively correlated with ADIPOQ and the strength of the correlation declined with aging. In contrast, the association between UCP1 and LEP was insignificant in young and middle-aged groups, but became significantly correlated in the older people group. We also found a positive correlation between UCP1 and PRDM16.
    CONCLUSIONS: PRDM16 and UCP1, despite their key functions in adipose browning, exhibit differential clinical correlations with metabolic features in human WAT in an age-dependent manner. These two genes may participate in the pathogenesis of aging-related metabolic diseases, but with distinct mechanisms.
    Keywords:  Adipokine; Aging; PRDM16; UCP1; Visceral adipose tissue
  6. Free Radic Biol Med. 2023 Feb 02. pii: S0891-5849(23)00049-7. [Epub ahead of print]
      Mitochondrial aconitase (ACO2) has been postulated as a redox sensor in the tricarboxylic acid cycle. Its high sensitivity towards reactive oxygen and nitrogen species is due to its particularly labile [4Fe-4S]2+ prosthetic group which yields an inactive [3Fe-4S]+ cluster upon oxidation. Moreover, ACO2 was found as a main oxidant target during aging and in pathologies where mitochondrial dysfunction is implied. Herein, we report the expression and characterization of recombinant human ACO2 and its interaction with frataxin (FXN), a protein that participates in the de novo biosynthesis of Fe-S clusters. A high yield of pure ACO2 (≥99%, 22 ± 2 U/mg) was obtained and kinetic parameters for citrate, isocitrate, and cis-aconitate were determined. Superoxide, carbonate radical, peroxynitrite, and hydrogen peroxide reacted with ACO2 with second-order rate constants of 108, 108, 105, and 102 M-1 s-1, respectively. Temperature-induced unfolding assessed by tryptophan fluorescence of ACO2 resulted in apparent melting temperatures of 51.1 ± 0.5 and 43.6 ± 0.2 °C for [4Fe-4S]2+ and [3Fe-4S]+ states of ACO2, sustaining lower thermal stability upon cluster oxidation. Differences in protein dynamics produced by the Fe-S cluster redox state were addressed by molecular dynamics simulations. Reactivation of [3Fe-4S]+-ACO2 by FXN was verified by activation assays and direct iron-dependent interaction was confirmed by protein-protein interaction ELISA and fluorescence spectroscopic assays. Multimer modeling and protein-protein docking predicted an ACO2-FXN complex where the metal ion binding region of FXN approaches the [3Fe-4S]+ cluster, supporting that FXN is a partner for reactivation of ACO2 upon oxidative cluster inactivation.
    Keywords:  Frataxin; Iron-sulfur protein; Mitochondria; Mitochondrial aconitase; Tricarboxylic acid cycle (TCA cycle) (Krebs cycle); protein‐protein interaction
  7. Biophys J. 2023 Feb 06. pii: S0006-3495(23)00095-4. [Epub ahead of print]
      Members of the fatty acid binding protein (FABP) family function as intracellular transporters of long chain fatty acids and other hydrophobic molecules to different cellular compartments. Brain fatty acid binding protein (FABP7) exhibits ligand-directed differences in cellular transport. For example, when FABP7 binds to docosahexaenoic acid (DHA), the complex relocates to the nucleus and influences transcriptional activity, whereas FABP7 bound with monosaturated fatty acids remains in the cytosol. Preferential binding of FABP7 to polyunsaturated fatty acids like DHA has been previously observed and is thought to play a role in differential localization. However, we find that at 37°C, FABP7 does not display strong selectivity, suggesting that the conformational ensemble of FABP7 and its perturbation upon binding may be important. We use molecular dynamics simulations, NMR, and a variety of biophysical techniques to better understand the conformational ensemble of FABP7, how it is perturbed by fatty acid binding, and how this may be related to ligand-directed transport. We find that FABP7 has high degree of confrontational heterogeneity that is substantially reduced upon ligand binding. We also observe substantial heterogeneity in ligand binding poses, which is consistent with our finding that ligand binding is resistant to mutations in key polar residues in the binding pocket. Our NMR experiments show that DHA binding leads to chemical shift perturbations in residues near the nuclear localization signal, which may point toward a mechanism of differential transport.
  8. Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00011-9. [Epub ahead of print]
      Mitochondrial function generates an important fraction of the heat that contributes to cellular and organismal temperature maintenance, but the actual values of this parameter reached in the organelles is a matter of debate. The studies addressing this issue have reported divergent results: from detecting in the organelles the same temperature as the cell average or the incubation temperature, to increasing differences of up to 10 degrees above the incubation value. Theoretical calculations based on physical laws exclude the possibility of relevant temperature gradients between mitochondria and their surroundings. These facts have given rise to a conundrum or paradox about hot mitochondria. We have examined by Blue-Native electrophoresis, both in intact cells and in isolated organelles, the stability of respiratory complexes and supercomplexes at different temperatures to obtain information about their tolerance to heat stress. We observe that, upon incubation at values above 43 °C and after relatively short periods, respiratory complexes, and especially complex I and its supercomplexes, are unstable even when the respiratory activity is inhibited. These results support the conclusion that high temperatures (> 43 °C) cause damage to mitochondrial structure and function and question the proposal that these organelles can physiologically work at close to 50 °C.
    Keywords:  hyperthermia; mitochondria; respiratory complex; stability; supercomplex; temperature
  9. Cells. 2023 Jan 30. pii: 446. [Epub ahead of print]12(3):
      Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders.
    Keywords:  15dPGJ2; 15dPGJ3; FAHFA; PGI2; TXA2; brown adipocyte; conversion; white adipocyte