bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–06–08
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. A cold-inducible phospholipid-protein interaction in brown fat mitochondria optimizes thermogenic capacity.
  2. Mitochondrial Calcium Uniporter is Required for Thermogenic Adaptation Mediated by Reactive Oxygen Species Signaling.
  3. Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
  4. Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
  5. MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT.
  6. Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
  7. Oxidative stress characterizes the dysfunction of thermogenic adipose tissue in a mouse model of down syndrome.
  1. bioRxiv. 2025 May 18. pii: 2025.05.15.654206. [Epub ahead of print]
    A cold-inducible phospholipid-protein interaction in brown fat mitochondria optimizes thermogenic capacity.
    Yuta Shimanaka, Marcus J Tol, Christian Rocha-Roa, Matthew J Jellinek, Liujuan Cui, Aaron Bender, Alexander H Bedard, Madeleine G Milner, Bruno Melillo, Bassem M Shoucri, Adrian Wong, Kevin J Williams, Linsey Stiles, Michael Shum, Thomas A Weston, Whitaker Cohn, Julian P Whitelegge, Itay Budin, Ambre M Bertholet, Benjamin F Cravatt, Stephen G Young, Sander M Houten, Carmen Argmann, David A Ford, Marc Liesa, Orian S Shirihai, Stefano Vanni, Peter Tontonoz.
      Cold stress elicits dynamic remodeling of the mitochondrial lipidome in brown adipose tissue (BAT), marked by an increase in arachidonoyl-phosphatidylethanolamine (AA-PE). However, the function of membrane lipid rewiring in thermoregulatory physiology has been a longstanding mystery. Here, we identify LPCAT3 as a cold-regulated O-acyltransferase driving the highly selective accrual of AA-PE in BAT mitochondria. Lipid-based proteomics, molecular dynamics simulations, and bioenergetic analyses reveal that AA-PE partitions at the COX4I1 interface of the Cytochrome c oxidase complex, enhancing electron transport chain (ETC) efficiency. Accordingly, fat-specific Lpcat3 -knockout mice have defects in respiratory-dependent BAT thermogenesis and cold tolerance, despite intact β-adrenergic signaling and UCP1 function. Under cold acclimation, Lpcat3 -/- BAT exhibits ETC dysfunction and activation of the integrated stress-response. Thus, our study illuminates a cold-regulated lipid-protein interaction as a gating factor in UCP1-dependent thermogenesis.
    DOI:  https://doi.org/10.1101/2025.05.15.654206
  2. J Lipid Res. 2025 May 29. pii: S0022-2275(25)00094-X. [Epub ahead of print] 100834
    Mitochondrial Calcium Uniporter is Required for Thermogenic Adaptation Mediated by Reactive Oxygen Species Signaling.
    Suji Kim, Seung-Kuy Cha, Kyu-Sang Park, Jun Namkung.
      Mitochondrial Ca2+ influx via mitochondrial calcium uniporter (MCU) accelerates mitochondrial biogenesis and energy metabolism. Nevertheless, the molecular mechanism of MCU-dependent mitochondrial activation and thermogenesis in thermogenic adipose tissues remains elusive. In this study, we demonstrate that MCU governs mitochondrial functions in brown and beige adipocytes via the formation of mitochondrial reactive oxygen species (mtROS). Mice with a brown adipose tissue-specific Mcu knockout (Mcu BKO) mice exhibited decreased oxygen consumption and heat production, accompanied by downregulation of genes related to β-oxidation and thermogenesis. Furthermore, Mcu BKO mice, exhibiting a reduction in mtROS, showed defective thermogenic responses to cold exposure or β-adrenergic stimulation. Downregulation of thermogenic genes including Ucp1 in Mcu BKO mice can be rescued by exogenous ROS through AMP-activated protein kinase (AMPK) activation. Collectively, our results suggest that MCU modulates mtROS formation, which in turn mediates mitonuclear signaling to cellular response with mitochondrial activation.
    Keywords:  Adipocytes; Adipose tissue; Lipolysis and fatty acid metabolism; Mitochondria; Obesity; brown
    DOI:  https://doi.org/10.1016/j.jlr.2025.100834
  3. Nat Metab. 2025 Jun 03.
    Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
    Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Prabhakar Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Bandy Chen, Maxim N Artyomov, Fahmeed Hyder, Tamas L Horvath, Marc Schneeberger, Yuki Sugiura, Vishwa Deep Dixit.
      Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
    DOI:  https://doi.org/10.1038/s42255-025-01297-8
  4. Nat Commun. 2025 Jun 04. 16(1): 5206
    Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
    Mingqiang Lai, Wu Zhou, Wenchong Zou, Lianlian Qiu, Zhaoyu Liang, Wanyi Chen, Yiqing Wang, Bin Guo, Chaoran Zhao, Sheng Zhang, Pinglin Lai, Le Hu, Xiaolin Liu, Yu Jiang, Yinghua Chen, Min-Jun Huang, Xiaochun Bai, Zhipeng Zou.
      Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfactomedin-4), a risk gene in human obesity, causes BAT dysfunction and reduces whole-body thermogenesis, predisposing to obesity in mice. Mechanistically, BAT-derived OLFM4 traps Noggin, an endogenous inhibitor of BMPs, liberating BMP7-BMPR1B signaling to promote SC differentiation. Conversely, Olfm4 loss reduced BMP7 signaling in mature SCs, leading to MEK/ERK-dependent dedifferentiation and dysfunction, ultimately impairing both sensory and sympathetic innervation. Thermoneutrality exposure reduces Olfm4 expression in BAT, resulting in a similar phenotype. MEK/ERK inhibition, ERK1 depletion, or cold exposure reverses this SC dedifferentiation, enhancing resistance to obesity. These findings suggest that this neurotrophic BAT-SC crosstalk controls thermoadaptive BAT innervation. Reactivating OLFM4 signaling may be a promising therapeutic strategy for obesity and related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60474-1
  5. Nat Commun. 2025 May 31. 16(1): 5063
    MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT.
    Andrea Ninni, Fabio Zaccaria, Luca Verteramo, Francesca Sciarretta, Loreana Sanches Silveira, José Cesar Rosa-Neto, Simone Carotti, Lorenzo Nevi, Paolo Grumati, Satish Patel, Giulia Carrera, Alessandro Sgambato, Donatella Lucchetti, Filomena Colella, Ilenia Severi, Martina Senzacqua, Antonio Giordano, Sergio Bernardini, Claudia Di Biagio, Flavia Tortolici, Giuseppe Rizzo, Clement Cochain, Valerio Chiurchiù, Stoyan Ivanov, Beiyan Zhou, Jesse W Williams, David B Savage, Katia Aquilano, Daniele Lettieri-Barbato.
      Macrophages are key regulators of adipose tissue plasticity. Obesity impairs brown adipose tissue (BAT) function in humans, yet macrophage-mediated mechanisms remain elusive. Here, we introduce MACanalyzeR, a single-cell RNA sequencing (scRNAseq) tool designed for comprehensive monocyte/macrophage metabolic profiling. Applying MACanalyzeR to BAT from obese male murine models (db/db and HFD-fed mice), we identify lipid-associated macrophages (LAMs) with foamy characteristics. Unlike db/db BAT LAMs, those in HFD BAT correlate with thermogenic gene expression and PPAR signaling activation. A distinct PpargHIGH LAM subcluster progressively accumulates in thermogenically active BAT. Macrophage-specific Pparg depletion disrupts BAT thermogenesis, inducing a white-like phenotype and metabolic dysfunctions. Mechanistically, PpargHIGH LAMs secrete GDF15, a key regulator of BAT identity and lipid metabolism under high-energy demand. Our study establishes MACanalyzeR as a powerful tool for immunometabolic interrogation and identifies PpargHIGH LAMs as critical mediators of BAT homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-60295-2
  6. Nat Commun. 2025 Jun 05. 16(1): 5209
    Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca2+ import and H+ efflux.
    Ran Chen, Bin Liu, Dawid Jaślan, Lucija Kucej, Veronika Kudrina, Belinda Warnke, Yvonne E Klingl, Arnas Petrauskas, Sandra Prat Castro, Kenji Maeda, Christian Grimm, Marja Jäättelä.
      The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how lysosomes replenish their calcium stores in placental mammals has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the cytosol. These data indicate that in addition to its previously identified role in the glycosylation of proteins and lipids in the Golgi, a fraction of TMEM165 localizes on the lysosomal limiting membrane, where its putative calcium/proton antiporter activity plays an essential role in the regulation of intracellular ion homeostasis and cell survival.
    DOI:  https://doi.org/10.1038/s41467-025-60349-5
  7. Free Radic Biol Med. 2025 May 31. pii: S0891-5849(25)00736-1. [Epub ahead of print]237 101-109
    Oxidative stress characterizes the dysfunction of thermogenic adipose tissue in a mouse model of down syndrome.
    S Castelli, A Tramutola, M Perluigi, M G Bacalini, M R Ciriolo, F Ciccarone.
      Down syndrome (DS) is associated with intellectual disability and multiple metabolic abnormalities, including obesity and early-onset type 2 diabetes. Gene dosage effects resulting from trisomy 21 may contribute to metabolic dysregulation in DS by impairing the function of key organs involved in systemic energy homeostasis. Brown and beige adipocytes, which are specialized for thermogenesis, dissipate energy through the oxidation of fatty acids and glucose, and are thus protective against metabolic diseases. In this study, we investigated the thermogenic potential of brown adipose tissue (BAT) in the Ts2Cje mouse model of DS. DS BAT exhibited morphological and functional signs of impairment, including enlarged lipid droplets and reduced expression of thermogenic proteins, consistent with a whitening phenotype. These changes were accompanied by decreased mitochondrial fission, suppressed triglyceride and glucose catabolism, and blunted insulin signaling. Subcutaneous adipose tissue, in which beige adipocytes are distributed, also showed signs of degeneration in DS mice, with a marked increase in senescence and inflammatory markers. In both adipose depots, superoxide dismutase 1 (SOD1), a gene triplicated in DS, was significantly upregulated and positively correlated with markers of lipid peroxidation and adipose tissue dysfunction. Together, these findings suggest that oxidative stress, driven in part by SOD1 overexpression, may compromise the thermogenic function of adipose tissue in DS, thereby contributing to the development of metabolic disorders in this condition.
    Keywords:  BAT whitening; Brown adipose tissue; Lipid peroxidation; SOD1; Trisomy 21
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.432
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