bims-mimbat 2023-02-19 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023–02–19
eight papers selected by
José Carlos de Lima-Júnior, Washington University

Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.
Cold exposure induces browning of bovine subcutaneous white fat in vivo and in vitro.
Torque generation mechanism in Fo motor of ATP synthase elucidated by free-energy and Coulomb-energy landscapes along the c-ring rotation.
Ectotherm mitochondrial economy and responses to global warming.
Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT).
Analysis of differential metabolites and metabolic pathways in adipose tissue of tree shrews (Tupaia belangeri) under gradient cooling acclimation.
Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.
Molecular mechanism and energetics of coupling between substrate binding and product release in the F1-ATPase catalytic cycle.

Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2219833120

Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.

Wenxin Song, Ye Yang, Patrick Heizer, Yiping Tu, Thomas A Weston, Joonyoung R Kim, Priscilla Munguia, Hyesoo Jung, Jared L-C Fong, Caitlyn Tran, Michael Ploug, Anne P Beigneux, Stephen G Young, Loren G Fong.

  Lipoprotein lipase (LPL) is secreted into the interstitial spaces by parenchymal cells and then transported into capillaries by GPIHBP1. LPL carries out the lipolytic processing of triglyceride (TG)-rich lipoproteins (TRLs), but the tissue-specific regulation of LPL is incompletely understood. Plasma levels of TG hydrolase activity after heparin injection are often used to draw inferences about intravascular LPL levels, but the validity of these inferences is unclear. Moreover, plasma TG hydrolase activity levels are not helpful for understanding LPL regulation in specific tissues. Here, we sought to elucidate LPL regulation under thermoneutral conditions (30 °C). To pursue this objective, we developed an antibody-based method to quantify (in a direct fashion) LPL levels inside capillaries. At 30 °C, intracapillary LPL levels fell sharply in brown adipose tissue (BAT) but not heart. The reduced intracapillary LPL levels were accompanied by reduced margination of TRLs along capillaries. ANGPTL4 expression in BAT increased fourfold at 30 °C, suggesting a potential explanation for the lower intracapillary LPL levels. Consistent with that idea, Angptl4 deficiency normalized both LPL levels and TRL margination in BAT at 30 °C. In Gpihbp1-/- mice housed at 30 °C, we observed an ANGPTL4-dependent decrease in LPL levels within the interstitial spaces of BAT, providing in vivo proof that ANGPTL4 regulates LPL levels before LPL transport into capillaries. In conclusion, our studies have illuminated intracapillary LPL regulation under thermoneutral conditions. Our approaches will be useful for defining the impact of genetic variation and metabolic disease on intracapillary LPL levels and TRL processing.

Keywords:  ANGPTL4; brown adipose tissue; intravascular lipolysis; thermoneutral; triglyceride hydrolysis

DOI:  https://doi.org/10.1073/pnas.2219833120
J Therm Biol. 2023 Feb;pii: S0306-4565(22)00260-1. [Epub ahead of print]112 103446

Cold exposure induces browning of bovine subcutaneous white fat in vivo and in vitro.

Tingting Li, Hui Bai, Liang Yang, Hongzhuang Wang, Shengjuan Wei, Peishi Yan.

  White adipocytes can be transformed into beige adipocytes through the process of browning under cold exposure. To investigate the effects and underlying mechanisms of cold exposure on subcutaneous white fat in cattle, in vitro and in vivo studies were performed. Eight bulls of Jinjiang cattle breed (Bos taurus) aged 18 months were allocated to the control group (n = 4, autumn) or the cold group (n = 4, winter) by different slaughter seasons. Biochemical and histomorphological parameters were detected in blood and backfat samples. Subcutaneous adipocytes from Simental cattle (Bos taurus) were then isolated and cultured at a normal body temperature (37 °C) and at a cold temperature (31 °C) in vitro. In the in vivo study, cold exposure stimulated subcutaneous white adipose tissue (sWAT) browning by reducing adipocyte sizes and up-regulating the expression levels of browning-specific makers (UCP1, PRDM16, and PGC-1α) in cattle. In addition, cold-exposed cattle displayed lower lipogenesis transcriptional regulator levels (PPARγ and CEBPα) and higher lipolysis regulator levels (HSL) in sWAT. In the in vitro study, cold temperature inhibited subcutaneous white adipocytes (sWA) adipogenic differentiation by reducing lipid contents and decreasing the expression of adipogenic marker genes and proteins. Furthermore, cold temperature led to sWA browning which was characterized by increased browning-related genes, mitochondrial contents, and mitochondrial biogenesis-specific markers. In addition, p38 MAPK signaling pathway activity was stimulated by the incubation in cold temperature for 6 h in sWA. We concluded that the cold-induced browning of the subcutaneous white fat was beneficial to the production of heat and the maintenance of body temperature regulation in cattle.

Keywords:  Adipocytes; Browning; Cold temperature; Mitochondrial biogenesis; Subcutaneous white adipose tissue; Thermogenesis

DOI:  https://doi.org/10.1016/j.jtherbio.2022.103446
Biochem Biophys Res Commun. 2023 Feb 03. pii: S0006-291X(23)00138-9. [Epub ahead of print]651 56-61

Torque generation mechanism in Fo motor of ATP synthase elucidated by free-energy and Coulomb-energy landscapes along the c-ring rotation.

Yukinari Kamiyama, Dan Parkin, Mitsunori Takano.

  Fo portion of ATP synthase is a proton-motive rotary motor. The Coulombic attraction between the conserved acidic residues in the c-ring and the arginine in the a-subunit (aR) was early proposed to drive the c-ring rotation relative to the a-subunit, and has been actually observed in our previous molecular dynamics simulation with full atomistic description of Fo embedded in the membrane. In this study, to quantify the driving force, we conducted the umbrella sampling (US) and obtained the free-energy landscape for the c-ring rotation. We first show that the free-energy gradient toward the ATP-synthesis direction appears in the deprotonated state of cE. Using the sampled snapshots that cover a wide range of the rotational angle, we further analyzed the rotational-angle dependence of the hydration and the protonation states and obtained the Coulomb-energy landscapes with a focus on the cE-aR interaction. The results indicate that both the Coulombic solvation energy of cE and the interaction energy between cE and aR contribute to the torque generation for the c-ring rotation.

Keywords:  Energy landscape; GB model; Molecular dynamics simulation; Proton motive force; Solvation; pK(a)

DOI:  https://doi.org/10.1016/j.bbrc.2023.01.085
Acta Physiol (Oxf). 2023 Feb 15. e13950

Ectotherm mitochondrial economy and responses to global warming.

Inna M Sokolova.

  Temperature is a key abiotic factor affecting ecology, biogeography and evolution of species. Alterations of energy metabolism play an important role in adaptations and plastic responses to temperature shifts on different time scales. Mitochondrial metabolism plays a key role in bioenergetics and redox balance making these organelles an important determinant of organismal performances such as growth, locomotion or development. Here I analyze the impacts of environmental temperature on the mitochondrial functions (including oxidative phosphorylation, proton leak, production of reactive oxygen species and ATP synthesis) of ectotherms and discuss the mechanisms underlying negative shifts in the mitochondrial energy economy caused by supraoptimal temperatures. Due to the differences in the thermal sensitivity of different mitochondrial processes, elevated temperatures (beyond the species- and population-specific optimal range) cause reallocation of the electron flux and the protonmotive force (Δp) in a way that decreases ATP synthesis efficiency, elevates the relative cost of the mitochondrial maintenance, causes excessive production of reactive oxygen species (ROS) and raises energy cost for antioxidant defense. These shifts in the mitochondrial energy economy might have negative consequences for the organismal fitness traits such as the thermal tolerance or growth. Correlation between the thermal sensitivity indices of the mitochondria and the whole organism indicate that these traits experience similar selective pressures but further investigations are needed to establish whether there is a cause-effect relationship between the mitochondrial failure and loss of organismal performance during temperature change.

Keywords:  ATP synthesis; Mitochondrial proton leak; animals; energy trade-off; mitochondrial efficiency; oxidative phosphorylation; oxidative stress; reactive oxygen species; temperature

DOI:  https://doi.org/10.1111/apha.13950
bioRxiv. 2023 Feb 03. pii: 2023.02.01.525989. [Epub ahead of print]

Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT).

Gavin Pharaoh, Varun Kamat, Sricharan Kannan, Rudolph S Stuppard, Jeremy Whitson, Miguel Martin-Perez, Wei-Jun Qian, Michael J MacCoss, Judit Villen, Peter Rabinovitch, Matthew D Campbell, Ian R Sweet, David J Marcinek.

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.
Abstract Figure:

DOI: https://doi.org/10.1101/2023.02.01.525989
J Therm Biol. 2023 Feb;pii: S0306-4565(22)00220-0. [Epub ahead of print]112 103406

Analysis of differential metabolites and metabolic pathways in adipose tissue of tree shrews (Tupaia belangeri) under gradient cooling acclimation.

Dongmin Hou, Huibao Chen, Ting Jia, Lin Zhang, Wenrong Gao, Simeng Chen, Wanlong Zhu.

  In order to investigate the influence of gradient cooling acclimation on body mass regulation in tree shrews (Tupaia belangeri), white adipose tissue (WAT) and brown adipose tissue (BAT) in T. belangeri between the control group and gradient cooling acclimation group on day 56 were collected, body mass, food intake, thermogenic capacity, differential metabolites, and related metabolic pathways in WAT and BAT were measured, the changes of differential metabolites were analyzed by non-targeted metabolomics method based on liquid chromatography-mass spectrometry. The results shown that gradient cooling acclimation significantly increased body mass, food intake, resting metabolic rate (RMR), non-shivering thermogenesis (NST), and masses of WAT and BAT. 23 significant differential metabolites in WAT between the gradient cooling acclimation group and the control group, of which the relative contents of 13 differential metabolites were up-regulated and 10 differential metabolites were down-regulated. 27 significant differential metabolites in BAT, of which 18 differential metabolites decreased and 9 differential metabolites increased. 15 differential metabolic pathways in WAT, 8 differential metabolic pathways in BAT, and 4 differential metabolic pathways involved in both WAT and BAT, including Purine metabolism, Pyrimidine metabolism, Glycerol phosphate metabolism, Arginine and proline metabolism, respectively. All of the above results suggested that T. belangeri could use different metabolites of adipose tissue to withstand low temperature environments and enhance their survival.

Keywords:  BAT; Differential metabolites; Gradient cooling acclimation; Tupaia belangeri; WAT

DOI:  https://doi.org/10.1016/j.jtherbio.2022.103406
EMBO J. 2023 Feb 16. e112202

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

Felix Clemens Richter, Matthias Friedrich, Nadja Kampschulte, Klara Piletic, Ghada Alsaleh, Ramona Zummach, Julia Hecker, Mathilde Pohin, Nicholas Ilott, Irina Guschina, Sarah Karin Wideman, Errin Johnson, Mariana Borsa, Paula Hahn, Christophe Morriseau, Bruce D Hammock, Henk Simon Schipper, Claire M Edwards, Rudolf Zechner, Britta Siegmund, Carl Weidinger, Nils Helge Schebb, Fiona Powrie, Anna Katharina Simon.

  Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Keywords:  IL-10; adipocyte; autophagy; inflammation; oxylipin

DOI:  https://doi.org/10.15252/embj.2022112202
Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2215650120

Molecular mechanism and energetics of coupling between substrate binding and product release in the F1-ATPase catalytic cycle.

Michał Badocha, Miłosz Wieczór, Antoni Marciniak, Cyprian Kleist, Helmut Grubmüller, Jacek Czub.

  F1-ATPase is a motor protein that couples the rotation of its rotary [Formula: see text] subunit with ATP synthesis or hydrolysis. Single-molecule experiments indicate that nucleotide binding and release events occur almost simultaneously during the synthesis cycle, allowing the energy gain due to spontaneous binding of ADP to one catalytic [Formula: see text] subunit to be directly harnessed for driving the release of ATP from another rather than being dissipated as heat. Here, we examine the unknown mechanism of this coupling that is critical for an exceptionally high mechanochemical efficiency of F1-ATPase by means of all-atom free-energy simulations. We find that nondissipative and kinetically fast progression of the motor in the synthesis direction requires a concerted conformational change involving the closure of the ADP-binding [Formula: see text] subunit followed by the gradual opening of the ATP-releasing [Formula: see text] subunit over the course of the 30 to 40° rotary substep of the [Formula: see text] subunit. This rotary substep, preceding the ATP-dependent metastable state, allows for the recovery of a large portion of the ADP binding energy in the conformation of ATP-bound [Formula: see text] that gradually adopts the low-affinity conformation, captured also by the recent cryo-EM structure of this elusive state. The release of ATP from this nearly open conformation leads to its further opening, which enables the progression of the motor to the next catalytic metastable state. Our simulations explain this energy conversion mechanism in terms of intersubunit and ligand-protein interactions.

Keywords:  ATP synthase; bioenergetics; molecular dynamics; motor proteins

DOI:  https://doi.org/10.1073/pnas.2215650120