bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023‒11‒19
six papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue.
  2. MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
  3. Cristae dynamics is modulated in bioenergetically compromised mitochondria.
  4. A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders.
  5. HSP47 levels determine the degree of body adiposity.
  6. Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure.
  1. Function (Oxf). 2022 ;3(5): zqac037
    Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue.
    Valerie Politis-Barber, Heather L Petrick, Arthe Raajendiran, Genevieve J DesOrmeaux, Henver S Brunetta, Larissa M Dos Reis, Marcelo A Mori, David C Wright, Matthew J Watt, Graham P Holloway.
      Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β3-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.
    Keywords:  adipose tissue; beiging; browning; creatine; creatine kinase; energy expenditure; futile cycling; metabolism; mitochondria; mitochondrial bioenergetics
    DOI:  https://doi.org/10.1093/function/zqac037
  2. Cell Rep. 2023 Nov 16. pii: S2211-1247(23)01477-8. [Epub ahead of print]42(11): 113465
    MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
    Jiuzhou Huo, Vikram Prasad, Kelly M Grimes, Davy Vanhoutte, N Scott Blair, Suh-Chin Lin, Michael J Bround, Donald M Bers, Jeffery D Molkentin.
      Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca2+ uniporter (MCU) and Ca2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased pyruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) overexpression in muscle of Mcub-deleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca2+ levels and substrate utilization that impacts total metabolic balance.
    Keywords:  CP: Metabolism; metabolism; mitochondria; obesity; skeletal muscle; substrate utilization
    DOI:  https://doi.org/10.1016/j.celrep.2023.113465
  3. Life Sci Alliance. 2024 Feb;pii: e202302386. [Epub ahead of print]7(2):
    Cristae dynamics is modulated in bioenergetically compromised mitochondria.
    Mathias Golombek, Thanos Tsigaras, Yulia Schaumkessel, Sebastian Hänsch, Stefanie Weidtkamp-Peters, Ruchika Anand, Andreas S Reichert, Arun Kumar Kondadi.
      Cristae membranes have been recently shown to undergo intramitochondrial merging and splitting events. Yet, the metabolic and bioenergetic factors regulating them are unclear. Here, we investigated whether and how cristae morphology and dynamics are dependent on oxidative phosphorylation (OXPHOS) complexes, the mitochondrial membrane potential (ΔΨm), and the ADP/ATP nucleotide translocator. Advanced live-cell STED nanoscopy combined with in-depth quantification were employed to analyse cristae morphology and dynamics after treatment of mammalian cells with rotenone, antimycin A, oligomycin A, and CCCP. This led to formation of enlarged mitochondria along with reduced cristae density but did not impair cristae dynamics. CCCP treatment leading to ΔΨm abrogation even enhanced cristae dynamics showing its ΔΨm-independent nature. Inhibition of OXPHOS complexes was accompanied by reduced ATP levels but did not affect cristae dynamics. However, inhibition of ADP/ATP exchange led to aberrant cristae morphology and impaired cristae dynamics in a mitochondrial subset. In sum, we provide quantitative data of cristae membrane remodelling under different conditions supporting an important interplay between OXPHOS, metabolite exchange, and cristae membrane dynamics.
    DOI:  https://doi.org/10.26508/lsa.202302386
  4. Obesity (Silver Spring). 2023 Nov 17.
    A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders.
    Ken Onodera, Yutaka Hasegawa, Nozomi Yokota, Shukuko Tamura, Hirofumi Kinno, Iwao Takahashi, Hiraku Chiba, Hirotatsu Kojima, Hideki Katagiri, Koji Nata, Yasushi Ishigaki.
      OBJECTIVE: Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.METHODS: To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes.
    RESULTS: We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).
    CONCLUSIONS: The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.
    DOI:  https://doi.org/10.1002/oby.23948
  5. Nat Commun. 2023 11 11. 14(1): 7319
    HSP47 levels determine the degree of body adiposity.
    Jihoon Shin, Shinichiro Toyoda, Yosuke Okuno, Reiko Hayashi, Shigeki Nishitani, Toshiharu Onodera, Haruyo Sakamoto, Shinya Ito, Sachiko Kobayashi, Hirofumi Nagao, Shunbun Kita, Michio Otsuki, Atsunori Fukuhara, Kazuhiro Nagata, Iichiro Shimomura.
      Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances.
    DOI:  https://doi.org/10.1038/s41467-023-43080-x
  6. Sci Signal. 2023 Nov 14. 16(811): eadh9399
    Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure.
    Alejandro Mata-Daboin, Tessa A C Garrud, Carlos Fernandez-Pena, Dieniffer Peixoto-Neves, M Dennis Leo, Angelica K Bernardelli, Purnima Singh, Kafait U Malik, Jonathan H Jaggar.
      Systemic blood pressure is acutely controlled by total peripheral resistance as determined by the diameter of small arteries and arterioles, the contractility of which is regulated by endothelial cells lining the lumen of blood vessels. We investigated the physiological functions of the chloride (Cl-) channel TMEM16A in endothelial cells. TMEM16A channels generated calcium (Ca2+)-activated Cl- currents in endothelial cells from control (TMEM16Afl/fl) mice that were absent in those from mice with tamoxifen-inducible, endothelial cell-specific knockout of TMEM16A (TMEM16A ecKO). TMEM16A currents in endothelial cells were activated by the muscarinic receptor agonist acetylcholine and an agonist of the Ca2+ channel TRPV4, which localized in nanoscale proximity with TMEM16A as assessed by single-molecule localization imaging of endothelial cells. Acetylcholine stimulated TMEM16A currents by activating Ca2+ influx through surface TRPV4 channels without altering the nanoscale properties of TMEM16A and TRPV4 surface clusters or their colocalization. In pressurized arteries, activation of TMEM16A channels in endothelial cells induced by acetylcholine; TRPV4 channel stimulation; or intraluminal ATP, another vasodilator, produced hyperpolarization and dilation. Furthermore, deficiency of TMEM16A channels in endothelial cells resulted in increased systemic blood pressure in conscious mice. These data indicate that vasodilators stimulate TRPV4 channels, leading to Ca2+-dependent activation of nearby TMEM16A channels in endothelial cells to produce arterial hyperpolarization, vasodilation, and reduced blood pressure. Thus, TMEM16A is an anion channel in endothelial cells that regulates arterial contractility and blood pressure.
    DOI:  https://doi.org/10.1126/scisignal.adh9399
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