bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024‒09‒22
six papers selected by
José Carlos de Lima-Júnior, Washington University
  1. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
  2. Identification of genes supporting cold resistance of mammalian cells: lessons from a hibernator.
  3. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
  4. Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
  5. Plasma endocannabinoids are independently associated with the metabolic function of white adipose tissue.
  6. Thermal and morphometric correlates of the extremely low rate of energy use in a wild frugivorous primate, the Mayotte lemur.
  1. EMBO J. 2024 Sep 16.
    IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
    Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt.
      While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
    Keywords:  Adipocytes; Metabolism; Mitochondria; Thermogenesis; UCP1
    DOI:  https://doi.org/10.1038/s44318-024-00215-0
  2. Cell Death Dis. 2024 Sep 19. 15(9): 685
    Identification of genes supporting cold resistance of mammalian cells: lessons from a hibernator.
    Masamitsu Sone, Nonoka Mitsuhashi, Yuki Sugiura, Yuta Matsuoka, Rae Maeda, Akari Yamauchi, Ryoto Okahashi, Junpei Yamashita, Kanako Sone, Sachiyo Enju, Daisuke Anegawa, Yoshifumi Yamaguchi.
      Susceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic deletion of or pharmacological inhibition of Gpx4 revealed that Gpx4 is necessary for suppressing lipid peroxidation specifically under cold in hamster cell lines. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, also accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans.
    DOI:  https://doi.org/10.1038/s41419-024-07059-w
  3. Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]
    Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.
      Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
    Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2024.08.029
  4. Nat Cardiovasc Res. 2024 Sep 18.
    Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
    Khanh V Doan, Timothy S Luongo, Thato T Ts'olo, Won Dong Lee, David W Frederick, Sarmistha Mukherjee, Gabriel K Adzika, Caroline E Perry, Ryan B Gaspar, Nicole Walker, Megan C Blair, Nicole Bye, James G Davis, Corey D Holman, Qingwei Chu, Lin Wang, Joshua D Rabinowitz, Daniel P Kelly, Thomas P Cappola, Kenneth B Margulies, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.
    DOI:  https://doi.org/10.1038/s44161-024-00542-9
  5. J Clin Endocrinol Metab. 2024 Sep 19. pii: dgae657. [Epub ahead of print]
    Plasma endocannabinoids are independently associated with the metabolic function of white adipose tissue.
    Dany Dion, Christophe Noll, Mélanie Fortin, Lounès Haroune, Sabrina Saibi, Philippe Sarret, André C Carpentier.
      CONTEXT: Little is known about the link between the endocannabinoid system and the in vivo metabolic function of white adipose tissue (WAT).OBJECTIVE: We aimed to evaluate whether endocannabinoids (EC) are linked to postprandial fatty acid metabolism and WAT metabolic function.
    DESIGN: Men and women, with (IGT, n=20) or without impaired glucose tolerance (NGT, n=20) underwent meal testing with oral and intravenous stable isotope palmitate tracers and positron emission tomography with intravenous [11C]-palmitate and oral [18F]-fluoro-thia-heptadecanoic acid to determine systemic and organ-specific dietary fatty acid (DFA) and non-esterified fatty acid (NEFA) metabolism and partitioning. We determined fasting and postprandial plasma levels of EC by UHPLC-MS/MS.
    RESULTS: All EC of the 2-monoacylglycerol (2-MAG) family displayed a progressive postprandial increase up to 360 min after meal intake that was more pronounced in women with IGT. N-acylethanolamine (NAE) levels decreased between fasting and 180 min, followed by a return to pre-prandial values at 360 min and were also increased in women with IGT. Postprandial area under the curve (AUC) of palmitate appearance rate was significantly and independently associated with postprandial AUC of anandamide (AEA; P=0.0003) and total energy expenditure (P=0.0009). DFA storage in abdominal subcutaneous adipose tissue was positively predicted by fasting 2-arachidonoylglycerol (2-AG; P<0.04).
    CONCLUSION: EC levels of the NAE family independently follow plasma NEFA metabolism, whereas 2-MAG closely follow the spillover of triglyceride-rich lipoprotein intravascular lipolytic products. Whether these associations are causal requires further investigation.
    Keywords:  Endocannabinoids; dietary fatty acids; fatty acid spillover; impaired glucose tolerance; insulin resistance; nonesterified fatty acids; obesity; positron emission tomography; postprandial fatty acid metabolism; prediabetes
    DOI:  https://doi.org/10.1210/clinem/dgae657
  6. Sci Rep. 2024 09 17. 14(1): 21700
    Thermal and morphometric correlates of the extremely low rate of energy use in a wild frugivorous primate, the Mayotte lemur.
    B Simmen, B Quintard, B Lefaux, L Tarnaud, G Correa-Pimpao, R Ibanez, S Blanc, A Zahariev.
      Primates spend on average half as much energy as other placental mammals while expressing a wide range of lifestyles. However, little is known about how primates adapt their rate of energy use in the context of natural environmental variations. Using doubly labelled water, behavioral and accelerometric methods, we measured the total energy expenditure (TEE) and body composition of a population of Eulemur fulvus (N = 12) living in an agroforest in Mayotte. We show that the TEE of this medium-sized cathemeral primate is one of the lowest recorded to date in eutherians. Regression models show that individual variation in the rate of energy use is predicted by fat-free mass, body size, thigh thickness and maximum temperature. TEE is positively correlated with increasing temperature, suggesting that thermoregulation is an important component of the energy budget of this frugivorous species. Mass-specific TEE is only 10% lower than that of a closely related species previously studied in a gallery forest, consistent with the assertion that TEE varies within narrow physiological limits. As lemur communities include many species with unique thermoregulatory adaptations, circadian and/or seasonal temperature variations may have constituted a major selective pressure on the evolution of lemur metabolic strategies.
    Keywords:  Body composition; Doubly labeled water; Fattening; Field metabolic rate; Heat stress; Seasonality
    DOI:  https://doi.org/10.1038/s41598-024-72189-2
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