bims-mimbat 2024-05-26 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒05‒26
seven papers selected by
José Carlos de Lima-Júnior, Washington University

Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.
Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting.
A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis.
Maintained mitochondrial integrity without oxygen in the anoxia tolerant crucian carp.
Lipidomics reveals the reshaping of the mitochondrial phospholipid profile in cells lacking OPA1 and Mitofusins.
Innervation of Adipocytes is Limited in Mouse Perivascular Adipose Tissue.
Imeglimin modulates mitochondria biology and facilitates mitokine secretion in 3T3-L1 adipocytes.

Elife. 2024 May 22. pii: RP87756. [Epub ahead of print]12

Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming.

Corey D Holman, Alexander P Sakers, Ryan P Calhoun, Lan Cheng, Ethan C Fein, Christopher Jacobs, Linus Tsai, Evan D Rosen, Patrick Seale.

  The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process in mice. We found that aging increases the expression of Cd9 and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with aging and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified Npr3, which encodes the natriuretic peptide clearance receptor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a resource for identifying cold and aging-regulated pathways in adipose tissue.

Keywords:  UCP1; aging; beige adipocyte; beige adipogenesis; cell biology; cold exposure; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.87756
EMBO Rep. 2024 May 20.

Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting.

Julia S Steinhoff, Carina Wagner, Henriette E Dähnhardt, Kristina Košić, Yueming Meng, Ulrike Taschler, Laura Pajed, Na Yang, Sascha Wulff, Marie F Kiefer, Konstantin M Petricek, Roberto E Flores, Chen Li, Sarah Dittrich, Manuela Sommerfeld, Hervé Guillou, Andrea Henze, Jens Raila, Sylvia J Wowro, Gabriele Schoiswohl, Achim Lass, Michael Schupp.

  Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.

Keywords:  Fasting; HSL; RBP4; Retinol; Vitamin A

DOI:  https://doi.org/10.1038/s44319-024-00158-x
Elife. 2024 May 23. pii: RP94187. [Epub ahead of print]13

A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis.

Eva Pyrihová, Martin S King, Alannah C King, M Rey Toleco, Mark van der Giezen, Edmund R S Kunji.

  Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight Phytophthora, and the human intestinal protozoan Blastocystis. In most eukaryotes, glycolysis is a strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in the production of NADH and ATP (Adenosine triphosphate). In contrast, stramenopiles have a branched glycolysis in which the enzymes of the pay-off phase are located in both the cytosol and the mitochondrial matrix. Here, we identify a mitochondrial carrier in Blastocystis that can transport glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, across the mitochondrial inner membrane, linking the cytosolic and mitochondrial branches of glycolysis. Comparative analyses with the phylogenetically related human mitochondrial oxoglutarate carrier (SLC25A11) and dicarboxylate carrier (SLC25A10) show that the glycolytic intermediate carrier has lost its ability to transport the canonical substrates malate and oxoglutarate. Blastocystis lacks several key components of oxidative phosphorylation required for the generation of mitochondrial ATP, such as complexes III and IV, ATP synthase, and ADP/ATP carriers. The presence of the glycolytic pay-off phase in the mitochondrial matrix generates ATP, which powers energy-requiring processes, such as macromolecular synthesis, as well as NADH, used by mitochondrial complex I to generate a proton motive force to drive the import of proteins and molecules. Given its unique substrate specificity and central role in carbon and energy metabolism, the carrier for glycolytic intermediates identified here represents a specific drug and pesticide target against stramenopile pathogens, which are of great economic importance.

Keywords:  Blastocystis; E. coli; S. cerevisiae; SLC25 mitochondrial carrier family; biochemistry; chemical biology; evolutionary biology; human; missing transport link; protists; thermostability shift assays; transport assays

DOI:  https://doi.org/10.7554/eLife.94187
J Exp Biol. 2024 May 23. pii: jeb.247409. [Epub ahead of print]

Maintained mitochondrial integrity without oxygen in the anoxia tolerant crucian carp.

Mark A Scott, Cathrine E Fagernes, Göran E Nilsson, Kåre-Olav Stensløkken.

  Very few vertebrates survive without oxygen (anoxia) for more than a few minutes. The crucian carp (Carassius carassius) survive months of anoxia at low temperatures and we hypothesised that they maintain mitochondrial membrane potential and function. Isolated crucian carp cardiomyocytes indeed maintained mitochondrial membrane potential after blocking complex-IV of the electron transport system with cyanide, while those of anoxia-intolerant trout depolarized. When complexes I-III were inhibited, crucian carp mitochondria depolarized, indicating that these complexes need to function during anoxia. Mitochondrial membrane potential depended on reversal of ATP synthase in chemical anoxia, as blocking with cyanide combined with oligomycin to inhibit ATP-synthase lead to depolarization. ATP-synthase activity was reduced in the heart after one week of anoxia in crucian carp, together with a downregulation of ATP-synthase subunit gene expression. However, the morphology of cardiac mitochondria were not affected by one-week anoxia, even with a large increase in mitofusin-2 expression. Cardiac citrate synthase activity was not affected by anoxia, while cytochrome-C oxidase activity was increased. We show how mitochondria respond to anoxia. A mechanistic understanding of how mitochondrial function can be maintained in anoxia may provide new perspectives to reduce mitochondrial damage in anoxia-sensitive organisms.

Keywords:  Heart; Metabolism; Mitochondria

DOI:  https://doi.org/10.1242/jeb.247409
J Lipid Res. 2024 May 17. pii: S0022-2275(24)00068-3. [Epub ahead of print] 100563

Lipidomics reveals the reshaping of the mitochondrial phospholipid profile in cells lacking OPA1 and Mitofusins.

Andrea Castellaneta, Ilario Losito, Vito Porcelli, Serena Barile, Alessandra Maresca, Valentina Del Dotto, Valentina Losacco, Ludovica Sofia Guadalupi, Cosima Damiana Calvano, David C Chan, Valerio Carelli, Luigi Palmieri, Tommaso R I Cataldi.

  Depletion or mutations of key proteins for mitochondrial fusion, like optic atrophy 1 (OPA1) and Mitofusins 1 and 2 (Mfn 1 and 2), are known to significantly impact the mitochondrial ultrastructure, suggesting alterations of their membranes' lipid profiles. In order to make an insight into this issue, we used hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray ionization-high resolution mass spectrometry to investigate the mitochondrial phospholipid (PL) profile of mouse embryonic fibroblasts (MEFs) knocked out for OPA1 and Mfn1/2 genes. 167 different sum compositions were recognized for the four major PL classes of mitochondria, namely phosphatidylcholines (PC, 63), phosphatidylethanolamines (PE, 55), phosphatidylinositols (PI, 21) and cardiolipins (CL, 28). A slight decrease in the CL/PC ratio was found for Mfn1/2-knock out mitochondria. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were subsequently used to further process HILIC-ESI-MS data. A progressive decrease in the incidence of alk(en)yl/acyl species in PC and PE classes and a general increase in the incidence of unsaturated acyl chains across all the investigated PL classes was inferred in OPA1 and Mfn1/2 knockouts compared to wild-type MEFs. These findings suggest a reshaping of the PL profile consistent with the changes observed in the mitochondrial ultrastructure when fusion proteins are absent. Based on the existing knowledge on the metabolism of mitochondrial phospholipids, we propose that fusion proteins, especially mitofusins, might influence the PL transfer between the mitochondria and the endoplasmic reticulum, likely in the context of mitochondria-associated membranes (MAMs).

Keywords:  OPA1; glycerophospholipids; high resolution mass spectrometry; hydrophilic interaction liquid chromatography; lipidomics; mitochondria; mitofusins; mouse embryonic fibroblasts; phospholipids; phospholipids/biosynthesis

DOI:  https://doi.org/10.1016/j.jlr.2024.100563
Am J Physiol Heart Circ Physiol. 2024 May 24.

Innervation of Adipocytes is Limited in Mouse Perivascular Adipose Tissue.

Marie Hanscom, Wilmarie Morales-Soto, Stephanie W Watts, William F Jackson, Brian D Gulbransen.

  BACKGROUND: Perivascular adipose tissue (PVAT) regulates vascular tone by releasing anticontractile factors. These anticontractile factors are driven by processes downstream of adipocyte stimulation by norepinephrine; however, whether norepinephrine originates from neural innervation or other sources is unknown. The goal of this study was to test the hypothesis that neurons innervating PVAT provide the adrenergic drive to stimulate adipocytes in aortic and mesenteric perivascular adipose tissue (aPVAT, mPVAT), and white adipose tissue (WAT).METHODS: Healthy male and female mice (8-13 weeks) were used in all experiments. Expression of genes associated with synaptic transmission were quantified by qPCR and adipocyte activity in response to neurotransmitters and neuron depolarization was assessed in AdipoqCre+;GCaMP5g-tdTf/WT mice. Immunostaining, tissue clearing, and transgenic reporter lines were used to assess anatomical relationships between nerves and adipocytes.
RESULTS: While synaptic transmission components genes are expressed in adipose tissues (aPVAT, mPVAT, WAT), strong nerve stimulation with electrical field stimulation does not significantly trigger calcium responses in adipocytes. However, norepinephrine consistently elicits strong calcium responses in adipocytes from all adipose tissues studied. Bethanechol induces minimal adipocyte responses. Imaging neural innervation using various techniques reveals that nerve fibers primarily run alongside blood vessels and rarely branch into the adipose tissue.
CONCLUSION: While nerve fibers are associated with blood vessels in adipose tissue, they demonstrate limited anatomical and functional interactions with adjacent adipocytes, challenging the concept of classical innervation. These findings dispute the significant involvement of neural input in regulating PVAT adipocyte function and emphasize alternative mechanisms governing adrenergic-driven anticontractile functions of PVAT.

Keywords:  Adipocytes; Hypertension; Neural Innervation; Perivascular Adipose Tissue

DOI:  https://doi.org/10.1152/ajpheart.00041.2024
Life Sci. 2024 May 18. pii: S0024-3205(24)00325-4. [Epub ahead of print]349 122735

Imeglimin modulates mitochondria biology and facilitates mitokine secretion in 3T3-L1 adipocytes.

Nobuhiko Takahashi, Atsushi P Kimura, Takayuki Yoshizaki, Kazumasa Ohmura.

  AIMS: Imeglimin, a novel antidiabetic drug, has recently been reported to affect pancreatic β-cells and hepatocytes. Adipose tissue plays a crucial role in systemic metabolism. However, its effect on adipocytes remains unexplored. Herein, we investigated the effects of imeglimin on adipocytes, particularly in the mitochondria.MAIN METHODS: The 3T3-L1 adipocytes were treated with imeglimin. Mitochondrial respiratory complex I activity and NAD+, NADH, and AMP levels were measured. Protein expression levels were determined by western blotting, mitochondrial DNA and mRNA expression levels were determined using quantitative polymerase chain reaction, and secreted adipocytokine and mitokine levels were determined using adipokine array and enzyme-linked immunosorbent assay.
KEY FINDINGS: Imeglimin inhibited complex I activity, decreased the NAD+/NADH ratio, and increased AMP levels, which were associated with the enhanced phosphorylation of AMP-activated protein kinase. In addition, imeglimin increased the mitochondrial DNA content and levels of mitochondrial transcription factor A and peroxisome proliferator-activated receptor-γ coactivator 1-α mRNA, which were abolished by Ly294002, a phosphoinositide 3-kinase inhibitor. Furthermore, imeglimin facilitated the expression levels of markers of the mitochondrial unfolded protein response, and the gene expression and secretion of two mitokines, fibroblast growth factor 21 and growth differentiation factor 15. The production of both mitokines was transcriptionally regulated and abolished by phosphoinositide 3-kinase and Akt inhibitors.
SIGNIFICANCE: Imeglimin modulates mitochondrial biology in adipocytes and may exert a mitohormetic effect through mitokine secretion.

Keywords:  Adipocyte; Imeglimin; Mitochondria; Mitokine

DOI:  https://doi.org/10.1016/j.lfs.2024.122735