bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–02–02
eleven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Cold induces brain region-selective cell activity-dependent lipid metabolism.
  2. Electrical homeostasis of the inner mitochondrial membrane potential.
  3. Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.
  4. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  5. Cryo-EM structure of the NDH-PSI-LHCI supercomplex from Spinacia oleracea.
  6. The roles of mitochondria in global and local intracellular calcium signalling.
  7. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  8. SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
  9. The juxtamembrane sequence of small ankyrin 1 mediates the binding of its cytoplasmic domain to SERCA1 and is required for inhibitory activity.
  10. Characterization of Subcutaneous and Visceral De-differentiated Fat Cells.
  11. Mitochondrial respiration in white adipose tissue is dependent on body mass index and tissue location in patients undergoing oncological or parietal digestive surgery.
  1. Elife. 2025 Jan 30. pii: RP98353. [Epub ahead of print]13
    Cold induces brain region-selective cell activity-dependent lipid metabolism.
    Hyeonyoung Min, Yale Y Yang, Yunlei Yang.
      It has been well documented that cold is an enhancer of lipid metabolism in peripheral tissues, yet its effect on central nervous system lipid dynamics is underexplored. It is well recognized that cold acclimations enhance adipocyte functions, including white adipose tissue lipid lipolysis and beiging, and brown adipose tissue thermogenesis in mammals. However, it remains unclear whether and how lipid metabolism in the brain is also under the control of ambient temperature. Here, we show that cold exposure predominantly increases the expressions of the lipid lipolysis genes and proteins within the paraventricular nucleus of the hypothalamus (PVH) in male mice. Mechanistically, by using innovatively combined brain-region selective pharmacology and in vivo time-lapse photometry monitoring of lipid metabolism, we find that cold activates cells within the PVH and pharmacological inactivation of cells blunts cold-induced effects on lipid peroxidation, accumulation of lipid droplets, and lipid lipolysis in the PVH. Together, these findings suggest that PVH lipid metabolism is cold sensitive and integral to cold-induced broader regulatory responses.
    Keywords:  cold; lipid metabolism; medicine; mouse; neuroscience; paraventricular of hypothalamus; photometry
    DOI:  https://doi.org/10.7554/eLife.98353
  2. Phys Biol. 2025 Jan 31. 22(2):
    Electrical homeostasis of the inner mitochondrial membrane potential.
    Peyman Fahimi, Lázaro A M Castanedo, P Thomas Vernier, Chérif F Matta.
      The electric potential across the inner mitochondrial membrane must be maintained within certain bounds for the proper functioning of the cell. A feedback control mechanism for the homeostasis of this membrane potential is proposed whereby an increase in the electric field decreases the rate-limiting steps of the electron transport chain (ETC). An increase in trans-membrane electric field limits the rate of proton pumping to the inter-membrane gap by slowing the ETC reactions and by intrinsically induced electroporation that depolarizes the inner membrane. The proposed feedback mechanism is akin to a Le Chatelier's-type principle of trans-membrane potential feedback control.
    Keywords:  chemiosmotic theory; electrical feedback control in biological systems; mitochondrial biophysics; mitochondrial electric potential; mitochondrial homeostasis
    DOI:  https://doi.org/10.1088/1478-3975/adaa47
  3. J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00065-1. [Epub ahead of print] 108218
    Mechanisms of dual modulatory effects of spermine on the mitochondrial calcium uniporter complex.
    Yung-Chi Tu, I-Chi Lee, Tsai-Wei Chang, Vivian Lee, Fan-Yi Chao, Eitel R Geltser, Ming-Feng Tsai.
      The mitochondrial Ca2+ uniporter is the Ca2+ channel responsible for mitochondrial Ca2+ uptake. It plays crucial physiological roles in regulating oxidative phosphorylation, intracellular Ca2+ signaling, and cell death. The uniporter contains the pore-forming MCU subunit, the auxiliary EMRE protein, and the regulatory MICU1 subunit, which blocks the MCU pore under resting cellular Ca2+ concentrations. It has been known for decades that spermine, a biological polyamine ubiquitously present in animal cells, can enhance mitochondrial Ca2+ uptake, but the underlying mechanisms remain incompletely understood. In this study, we demonstrate that spermine exerts both potentiation and inhibitory effects on the uniporter. At physiological concentrations, spermine binds to membranes and disrupts MCU-MICU1 interactions, thereby opening the uniporter to import more Ca2+. However, at millimolar concentrations, spermine also inhibits the uniporter by targeting the pore-forming region in a MICU1-independent manner. These findings provide molecular insights into how cells can use spermine to control the critical processes of mitochondrial Ca2+ signaling and homeostasis.
    Keywords:  calcium channel; cell signaling; channel activation; membrane biophysics; mitochondrial transport; polyamine
    DOI:  https://doi.org/10.1016/j.jbc.2025.108218
  4. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  5. Nat Struct Mol Biol. 2025 Jan 24.
    Cryo-EM structure of the NDH-PSI-LHCI supercomplex from Spinacia oleracea.
    Bianca Introini, Alexander Hahn, Werner Kühlbrandt.
      The nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase (NDH) complex is crucial for photosynthetic cyclic electron flow and respiration, transferring electrons from ferredoxin to plastoquinone while transporting H+ across the chloroplast membrane. This process boosts adenosine triphosphate production, regardless of NADPH levels. In flowering plants, NDH forms a supercomplex with photosystem I, enhancing its stability under high light. We report the cryo-electron microscopy structure of the NDH supercomplex in Spinacia oleracea at a resolution of 3.0-3.3 Å. The supercomplex consists of 41 protein subunits, 154 chlorophylls and 38 carotenoids. Subunit interactions are reinforced by 46 distinct lipids. The structure of NDH resembles that of mitochondrial complex I closely, including the quinol-binding site and an extensive internal aqueous passage for proton translocation. A well-resolved catalytic plastoquinone (PQ) occupies the PQ channel. The pronounced structural similarity to complex I sheds light on electron transfer and proton translocation within the NDH supercomplex.
    DOI:  https://doi.org/10.1038/s41594-024-01478-1
  6. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  7. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  8. Nat Commun. 2025 Jan 30. 16(1): 1181
    SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
    Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.
      Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.
    DOI:  https://doi.org/10.1038/s41467-025-56402-y
  9. J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00063-8. [Epub ahead of print] 108216
    The juxtamembrane sequence of small ankyrin 1 mediates the binding of its cytoplasmic domain to SERCA1 and is required for inhibitory activity.
    Yi Li, Nathan T Wright, Robert J Bloch.
      Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase1 (SERCA1) is responsible for the clearance of cytosolic Ca2+ in skeletal muscle. Due to its vital importance in regulating Ca2+ homeostasis, the regulation of SERCA1 has been intensively studied. Small ankyrin 1 (sAnk1, Ank1.5), a 17 kDa muscle-specific isoform of ANK1, binds to SERCA1 directly via both its transmembrane and cytoplasmic domains and inhibits SERCA1's ATPase activity. Here we characterize the interaction between the cytoplasmic domain of sAnk1 (sAnk1(29-155)) and SERCA1. The binding affinity for sAnk1 (29-155) to SERCA1 was 444 nM by blot overlay, about 7-fold weaker than the binding of sAnk1(29-155) to obscurin, a giant protein of the muscle cytoskeleton. Site-directed mutagenesis identified K38, H39, and H41, in the juxtamembrane region, as residues likely to mediate binding to SERCA1. These residues are not required for obscurin binding. Residues R64-K73, which do contribute to obscurin binding, are also required for binding to SERCA1, but only the hydrophobic residues in this sequence are required, not the positively charged residues necessary for obscurin binding. Circular dichroism analysis of sAnk1(29-155) indicates that most mutants show significant structural changes, with the exception of those containing alanines in place of K38, H39 and H41. Although the cytoplasmic domain of sAnk1 does not inhibit SERCA1's Ca2+-ATPase activity, with or without mutations in the juxtamembrane sequence, the inhibitory activity of full-length sAnk1 requires the WT juxtamembrane sequence. We used these data to model sAnk1 and the sAnk1-SERCA1 complex. Our results suggest that, in addition to its transmembrane domain, sAnk1 uses its juxtamembrane sequence and perhaps part of its obscurin binding site to bind to SERCA1, and that this binding contributes to their robust association in situ, as well as regulation of SERCA1's activity.
    Keywords:  Alphafold; Ca-ATPase; ankyrin; circular dichroism (CD); complex; membrane transport; sarcoplasmic reticulum (SR); skeletal muscle; structural model
    DOI:  https://doi.org/10.1016/j.jbc.2025.108216
  10. Mol Metab. 2025 Jan 28. pii: S2212-8778(25)00012-2. [Epub ahead of print] 102105
    Characterization of Subcutaneous and Visceral De-differentiated Fat Cells.
    Yan Li, Houyu Zhang, Carlos F Ibáñez, Meng Xie.
      The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown. Here, we show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-κB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs. These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.
    Keywords:  DFAT cell re-differentiation; DNA methylation; NF-κB; adipocyte de-differentiation; diet intervention; scRNA-seq/snRNA-seq
    DOI:  https://doi.org/10.1016/j.molmet.2025.102105
  11. FASEB J. 2025 Jan 31. 39(2): e70350
    Mitochondrial respiration in white adipose tissue is dependent on body mass index and tissue location in patients undergoing oncological or parietal digestive surgery.
    Lisa Guerrier, Ophélie Bacoeur-Ouzillou, Julianne Touron, Sami Mezher, Lucie Cassagnes, Aurélie Vieille-Marchiset, Stéphanie Chanon, Bruno Pereira, Denis Pezet, Alexandre Pinel, Johan Gagnière, Corinne Malpuech-Brugère, Ruddy Richard.
      Adipose tissue (AT), is a major endocrine organ that plays a key role in health and disease. However, adipose dysfunctions, especially altered energy metabolism, have been under-investigated as white adipocytes have relatively low mitochondrial density. Nevertheless, recent studies suggest that mitochondria could play a major role in AT disorders and that AT mitochondrial activity could depend on adiposity level and location. This clinical study aimed to evaluate mitochondrial respiration and metabolism in human visceral (vAT) and subcutaneous (scAT) AT and their relationship with body mass index (BMI). This clinical study enrolled 67 patients (30 females/37 males) scheduled for digestive surgery without chemotherapy and parietal infection. BMI ranged from 15.4 to 51.9 kg·m-2 and body composition was estimated by computed tomographic images. Mitochondrial respiration was measured in situ in digitonin-permeabilized AT using high-resolution respirometry and a substrate/inhibitor titration approach. Protein levels of mitochondrial and lipid metabolism key elements were evaluated by Western blot. Maximal mitochondrial respiration correlated negatively with BMI (p < .01) and AT area (p < .001) regardless of the anatomical location. However, oxidative phosphorylation respiration was significantly higher in vAT (2.22 ± 0.15 pmol·sec-1·mg-1) than scAT (1.79 ± 0.17 pmol·sec-1·mg-1) (p < 0.001). In line with oxygraphy results, there were higher levels of mitochondrial respiratory chain complexes in low-BMI patients and vAT. Mitochondrial respiration decreased with increasing BMI in both scAT and vAT, without sex-associated difference. Mitochondrial respiration appeared to be higher in vAT than scAT. These differences were both qualitative and quantitative. Clinical Trials Registration IDNCT05417581.
    Keywords:  body composition; body mass index; human; lipid metabolism; mitochondrial respiration; white adipose tissue
    DOI:  https://doi.org/10.1096/fj.202402243R
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