bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–03–30
ten papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
  2. A BCAA-haem axis regulates brown fat function.
  3. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  4. No UCP1 in the kidney.
  5. Oxidation of retromer complex controls mitochondrial translation.
  6. In situ architecture of the human prohibitin complex.
  7. Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
  8. Glutamate gating of AMPA-subtype iGluRs at physiological temperatures.
  9. PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
  10. The metabolically protective energy expenditure increase of Pik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis.
  1. Nat Metab. 2025 Mar 25.
    Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
    Dylan J Duerre, Julia K Hansen, Steven V John, Annie Jen, Noah D Carrillo, Hoang Bui, Yutong Bao, Matias Fabregat, J Leon Catrow, Li-Yu Chen, Katherine A Overmyer, Evgenia Shishkova, Quentinn Pearce, Mark P Keller, Richard A Anderson, Vincent L Cryns, Alan D Attie, James E Cox, Joshua J Coon, Jing Fan, Andrea Galmozzi.
      The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01253-6
  2. Nat Metab. 2025 Mar 25.
    A BCAA-haem axis regulates brown fat function.
      
    DOI:  https://doi.org/10.1038/s42255-025-01266-1
  3. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  4. Mol Metab. 2025 Mar 20. pii: S2212-8778(25)00034-1. [Epub ahead of print] 102127
    No UCP1 in the kidney.
    Celso Pereira Batista Sousa-Filho, Natasa Petrovic.
       OBJECTIVES: Several recent studies have indicated the presence of UCP1 in the kidney, challenging the paradigm that UCP1 is only found in brown and beige adipocytes and broadening the (patho)physiological significance of UCP1. The kidney localization has been the direct result of immunohistochemical investigations and an inferred outcome from multiple lines of reporter mice. These findings require confirmation and further physiological characterization.
    METHODS: We examined UCP1 expression in the kidney using immunohistochemistry and qPCR. Transversal sections through or near the kidney hilum, consistently including perirenal brown fat and adjacent kidney tissue, were analyzed with four UCP1 antibodies.
    RESULTS: In addition to detecting UCP1 in perirenal adipose tissue, we observed distinct immunopositive structures in the kidney with our in-house UCP1-antibody, 'C10', in apparent agreement with earlier reports. To corroborate this, we tested the C10-antibody on kidney sections from UCP1-ablated mice but found equal reactivity in these UCP1-negative tissues. We then tested the widely used antibody ab10983, previously employed in kidney studies. Also here, the positive signal persisted in UCP1-ablated mice, clearly invalidating earlier findings. UCP1 qPCR studies also failed to detect UCP1 mRNA above background. Finally, two highly specific antibodies, E9Z2V and EPR20381, accurately detected UCP1 in perirenal adipose tissue but showed no signal in the kidney.
    CONCLUSIONS: When appropriate controls are implemented, there is no evidence for the presence of UCP1 in the kidney. Consequently, this conclusion also implies that the results from UCP1 reporter mice, specifically regarding kidney expression of the UCP1 gene - though possibly applicable to other tissues - require reconfirmation before being accepted as evidence for the presence of UCP1 in non-adipose tissues.
    Keywords:  Antibody; Immunohistochemistry; Kidney; UCP1; brown adipose tissue
    DOI:  https://doi.org/10.1016/j.molmet.2025.102127
  5. Nature. 2025 Mar 26.
    Oxidation of retromer complex controls mitochondrial translation.
    Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan Vornbäumen, Zehra Ordulu, Anthony P Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N Pavlova, Michael Lawrence, Justin F Gainor, Sean A Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J Ott, Brian Liau, Liron Bar-Peled.
      Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
    DOI:  https://doi.org/10.1038/s41586-025-08756-y
  6. Nat Cell Biol. 2025 Mar 21.
    In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others. The human prohibitins prohibitin 1 and prohibitin 2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organization has remained elusive. Here we determined the molecular organization of the human prohibitin complex within the mitochondrial inner membrane using an integrative structural biology approach combining quantitative western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling. The proposed bell-shaped structure consists of 11 alternating prohibitin 1 and prohibitin 2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3% of the crista membrane area. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organization of the mitochondrial inner membrane.
    DOI:  https://doi.org/10.1038/s41556-025-01620-1
  7. Science. 2025 Mar 28. 387(6741): eadr8589
    Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
    Gianni M Castiglione, Xin Chen, Zhenhua Xu, Nadir H Dbouk, Anamika A Bose, David Carmona-Berrio, Emiliana E Chi, Lingli Zhou, Tatiana N Boronina, Robert N Cole, Shirley Wu, Abby D Liu, Thalia D Liu, Haining Lu, Ted Kalbfleisch, David Rinker, Antonis Rokas, Kyla Ortved, Elia J Duh.
      Horses are among nature's greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation-conserved in all extant equids-that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5'-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.
    DOI:  https://doi.org/10.1126/science.adr8589
  8. Nature. 2025 Mar 26.
    Glutamate gating of AMPA-subtype iGluRs at physiological temperatures.
    Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman, Edward C Twomey.
      Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission1. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction1,2. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.
    DOI:  https://doi.org/10.1038/s41586-025-08770-0
  9. Biochem Biophys Res Commun. 2025 Mar 21. pii: S0006-291X(25)00386-9. [Epub ahead of print]759 151672
    PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
    Jiaxin Cao, Nana Li, Ruolan Huang, Fengjuan Jia, Ziyi He, Wenlong Han, Wenzhang Liu, Songqiao Li, Weiye Wang, Weiyuan Ren, Bo Xia.
      Intramuscular fat (IMF) is a key determinant of meat quality in pigs, influencing characteristics such as tenderness, flavor, and marbling. The regulation of IMF deposition involves complex metabolic processes, with mitochondrial function playing a central role. PTEN-induced kinase 1 (PINK1), a protein involved in mitophagy and mitochondrial quality control, has recently been implicated in regulating fat deposition, although its role in IMF deposition in pigs remains unclear. This study investigates how PINK1 regulates IMF deposition by modulating mitochondrial-endoplasmic reticulum (ER) interactions. We utilized single-cell RNA sequencing to demonstrate that PINK1 is predominantly expressed in fibro-adipogenic progenitors (FAPs) and adipocytes, and its expression is negatively correlated with IMF content in multiple pig breeds. Knockdown of PINK1 in vivo led to increased intramuscular triglyceride content and enhanced adipogenic differentiation in primary porcine IMF cells. Additionally, PINK1 depletion resulted in impaired mitochondrial respiration, increased mitochondrial biogenesis, and disruption of mitochondria-ER contacts, further suggesting that PINK1 mediated of mitochondrial function and communication between mitochondria and ER is essential for controlling lipid deposition. These findings provide novel insights into the molecular mechanisms governing IMF accumulation and highlight PINK1 as a potential target for manipulating fat deposition in both agricultural and biomedical contexts.
    Keywords:  Intramuscular fat; Mitochondria-ER contacts; Mitophagy; PINK1; Pig
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151672
  10. Am J Physiol Endocrinol Metab. 2025 Mar 28.
    The metabolically protective energy expenditure increase of Pik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis.
    Ineke Luijten, Ami Onishi, Eleanor J McKay, Tore Bengtsson, Robert K Semple.
      Human SHORT syndrome is caused by dominant negative human PIK3R1 mutations that impair insulin-stimulated phosphoinositide 3-kinase (PI3K) activity. This produces severe insulin resistance (IR) and often reduced adiposity, commonly described as lipodystrophy. However unlike human primary lipodystrophies, SHORT syndrome does not feature fatty liver or dyslipidaemia. Pik3r1Y657*/WT (Pik3r1Y657*) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure on high fat feeding. We have hypothesised that this increased energy expenditure explains protection from lipotoxicity, and suggested that understanding its mechanism may offer novel approaches to mitigating the metabolic syndrome. We set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure in Pik3r1-related IR. Male and female Pik3r1Y657* mice challenged with a 45% fat diet for 3 weeks at 21°C showed reduced metabolic efficiency not explained by changes in food intake or physical activity. No changes were seen in thermoregulation, assessed by thermal imaging and a modified Scholander protocol. Ucp1- dependent thermogenesis, assessed by norepinephrine-induced oxygen consumption, was also unaltered. Housing at 30°C did not alter the metabolic phenotype of male Pik3r1Y657* mice, but led to lowered physical activity in female Pik3r1Y657* mice compared to controls. Nevertheless these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30°C was similar in Pik3r1Y657* and WT mice. We conclude that the likely metabolically protective 'energy leak' in Pik3r1-related IR is not caused by Ucp1- mediated BAT hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non Ucp1-mediated futile cycling.
    Keywords:  Insulin resistance; PI 3-Kinase; Pik3r1; brown adipose tissue; energy expenditure
    DOI:  https://doi.org/10.1152/ajpendo.00449.2024
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