bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–05–18
nine papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
  2. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
  3. The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.
  4. YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ.
  5. Molecular machineries shaping the mitochondrial inner membrane.
  6. Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress.
  7. Structural dynamics and permeability of the TRPV3 pentamer.
  8. Mitochondrial transfer in endothelial cells and vascular health.
  9. Electric field-induced pore constriction in the human Kv2.1 channel.
  1. Nat Metab. 2025 May 13.
    Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
    Anne Loft, Margo P Emont, Ada Weinstock, Adeline Divoux, Adhideb Ghosh, Allon Wagner, Ann V Hertzel, Babukrishna Maniyadath, Bart Deplancke, Boxiang Liu, Camilla Scheele, Carey Lumeng, Changhai Ding, Chenkai Ma, Christian Wolfrum, Clarissa Strieder-Barboza, Congru Li, Danh D Truong, David A Bernlohr, Elisabet Stener-Victorin, Erin E Kershaw, Esti Yeger-Lotem, Farnaz Shamsi, Hannah X Hui, Henrique Camara, Jiawei Zhong, Joanna Kalucka, Joseph A Ludwig, Julie A Semon, Jutta Jalkanen, Katie L Whytock, Kyle D Dumont, Lauren M Sparks, Lindsey A Muir, Lingzhao Fang, Lucas Massier, Luis R Saraiva, Marc D Beyer, Marc G Jeschke, Marcelo A Mori, Mariana Boroni, Martin J Walsh, Mary-Elizabeth Patti, Matthew D Lynes, Matthias Blüher, Mikael Rydén, Natnael Hamda, Nicole L Solimini, Niklas Mejhert, Peng Gao, Rana K Gupta, Rinki Murphy, Saeed Pirouzpanah, Silvia Corvera, Su'an Tang, Swapan K Das, Søren F Schmidt, Tao Zhang, Theodore M Nelson, Timothy E O'Sullivan, Vissarion Efthymiou, Wenjing Wang, Yihan Tong, Yu-Hua Tseng, Susanne Mandrup, Evan D Rosen.
      Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.
    DOI:  https://doi.org/10.1038/s42255-025-01296-9
  2. Cell Metab. 2025 May 08. pii: S1550-4131(25)00253-0. [Epub ahead of print]
    Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
    Jessica W Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Monther Abu-Remaileh, Judith A Simcox.
      Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
    Keywords:  BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.015
  3. EMBO J. 2025 May 12.
    The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.
    Jennie Dinh, Danielle Yi, Frances Lin, Pengya Xue, Nicholas D Holloway, Ying Xie, Nnejiuwa U Ibe, Hai P Nguyen, Jose A Viscarra, Yuhui Wang, Hei Sook Sul.
      Brown and beige adipose tissues are metabolically beneficial for increasing energy expenditure via thermogenesis, mainly through UCP1 (uncoupling protein 1). Here, we identify C16orf74, subsequently named MICT1 (microprotein for thermogenesis 1), as a microprotein that is specifically and highly expressed in brown adipose tissue (BAT) and is induced upon cold exposure. MICT1 interacts with protein phosphatase 2B (PP2B, calcineurin) through the docking motif PNIIIT, thereby interfering with dephosphorylation of the regulatory subunit of protein kinase A (PKA), RIIβ, and potentiating PKA activity in brown adipocytes. Overexpression of MICT1 in differentiated brown adipocytes promotes thermogenesis, showing increased oxygen consumption rate (OCR) with higher thermogenic gene expression during β3-adrenergic stimulation, while knockdown of MICT1 impairs thermogenic responses. Moreover, BAT-specific MICT1 ablation in mice suppresses thermogenic capacity to increase adiposity and insulin resistance. Conversely, MICT1 overexpression in BAT or treating mice with a chemical inhibitor that targets the PP2B docking motif of MICT1 enhances thermogenesis. This results in cold tolerance and increased energy expenditure, protection against diet-induced and genetic obesity and insulin resistance, thus suggesting a therapeutic potential of MICT1 targeting.
    Keywords:  Brown Adipose Tissue (Thermogenesis); C16orf74 (MICT1); Microprotein; PP2B (Calcineurin); Protein Kinase A (PKA)
    DOI:  https://doi.org/10.1038/s44318-025-00444-x
  4. EMBO J. 2025 May 12.
    YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ.
    Lihua Wang, Yuqin Wang, Kaixin Ding, Zhenzhi Li, Zhipeng Zhang, Xinzhi Li, Yue Song, Liwei Xie, Zheng Chen.
      Brown adipose tissue (BAT) plays a vital role in non-shivering thermogenesis and energy metabolism and is influenced by factors like environmental temperature, ageing, and obesity. However, the molecular mechanisms behind BAT development and thermogenesis are not fully understood. Our study identifies the m6A reader protein YTHDC1 as a crucial regulator of postnatal interscapular BAT development and energy metabolism in mice. YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR), thus protecting PPARγ from binding the E3 ubiquitin ligase ARIH2, and preventing its ubiquitin-mediated proteasomal degradation. Specifically, the ARIH2 RING2 domain is essential for PPARγ degradation, while PPARγ's A/B domain is necessary for their interaction. Deletion of Ythdc1 in BAT increases PPARγ degradation, impairing interscapular BAT development, thermogenesis, and overall energy expenditure. These findings reveal a novel mechanism by which YTHDC1 regulates BAT development and energy homeostasis independently of its m6A recognition function.
    Keywords:  Brown Adipose Tissue; Intrinsically Disordered Region; PPARγ; Thermogenesis; YTHDC1
    DOI:  https://doi.org/10.1038/s44318-025-00460-x
  5. Nat Rev Mol Cell Biol. 2025 May 14.
    Molecular machineries shaping the mitochondrial inner membrane.
    Oliver Daumke, Martin van der Laan.
      Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.
    DOI:  https://doi.org/10.1038/s41580-025-00854-z
  6. Nat Commun. 2025 May 14. 16(1): 4455
    Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress.
    Yixiao Zhuang, Xinyi Zhang, Shuang Zhang, Yunpeng Sun, Hui Wang, Yuxuan Chen, Hanyin Zhang, Penglai Zou, Yonghao Feng, Xiaodan Lu, Peijie Chen, Yi Xu, John Zhong Li, Huanqing Gao, Li Jin, Xingxing Kong.
      Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass spectrum and biochemical assays, we found that PARK7, a Parkinson's disease causative protein, could sense the temperature changes and interact with LAMP2A and HSC70, respectively, subsequently manipulate the activity of CMA. Knockout of Park7 specific in BAT promoted BAT whitening, leading to impaired insulin sensitivity and energy expenditure at thermoneutrality. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A reversed the effects induced by Park7 ablation. These findings suggest CMA is required for BAT to sustain thermoneutrality-induced whitening through degradation of PGC1α.
    DOI:  https://doi.org/10.1038/s41467-025-59618-0
  7. Nat Commun. 2025 May 15. 16(1): 4520
    Structural dynamics and permeability of the TRPV3 pentamer.
    Shifra Lansky, Zhaokun Wang, Oliver B Clarke, Christophe Chipot, Simon Scheuring.
      TRPV3 belongs to the large superfamily of tetrameric transient receptor potential (TRP) ion channels. Recently, using high-speed atomic force microscopy (HS-AFM), we discovered a rare and transient pentameric state for TRPV3 that is in equilibrium with the tetrameric state, and, using cryo-EM, we solved a low-resolution structure of the TRPV3 pentamer, in which, however, many residues were unresolved. Here, we present a higher resolution and more complete structure of the pentamer, revealing a domain-swapped architecture, a collapsed vanilloid binding site, and a large pore. Molecular dynamics simulations and potential of mean force calculations of the pentamer establish high protein dynamics and permeability to large cations. Subunit interface analysis, together with thermal denaturation experiments, led us to propose a molecular mechanism of the tetramer-to-pentamer transition, backed experimentally by HS-AFM observations. Collectively, our data demonstrate that the TRPV3 pentamer is in a hyper-activated state with unique, highly permissive permeation properties.
    DOI:  https://doi.org/10.1038/s41467-025-59798-9
  8. Trends Cell Biol. 2025 May 13. pii: S0962-8924(25)00105-9. [Epub ahead of print]
    Mitochondrial transfer in endothelial cells and vascular health.
    Gwang-Bum Im, Juan M Melero-Martin.
      Mitochondria play a vital role in cellular energy metabolism and vascular health, with their function directly influencing endothelial cell (EC) bioenergetics and integrity. Mitochondrial transfer has emerged as a key mechanism of intercellular communication, impacting angiogenesis, tissue repair, and cellular homeostasis. This review highlights recent findings on mitochondrial transfer, including natural mechanisms - such as tunneling nanotubes (TNTs) and extracellular vesicles (EVs) - and artificial approaches like mitochondrial transplantation. These processes enhance EC function and support vascularization under pathological conditions, including ischemia. While early clinical trials demonstrate therapeutic potential, challenges such as mitochondrial instability and scaling host-derived mitochondria persist. Continued research is essential to optimize mitochondrial transfer and advance its application as a therapeutic strategy for restoring vascular health.
    Keywords:  angiogenesis; endothelial cells; mitochondrial transfer; mitochondrial transplantation; vascular regeneration
    DOI:  https://doi.org/10.1016/j.tcb.2025.04.004
  9. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426744122
    Electric field-induced pore constriction in the human Kv2.1 channel.
    Venkata Shiva Mandala, Roderick MacKinnon.
      Gating in voltage-dependent ion channels is regulated by the transmembrane voltage. This form of regulation is enabled by voltage-sensing domains (VSDs) that respond to transmembrane voltage differences by changing their conformation and exerting force on the pore to open or close it. Here, we use cryogenic electron microscopy to study the neuronal Kv2.1 channel in lipid vesicles with and without a voltage difference across the membrane. Hyperpolarizing voltage differences displace the positively charged S4 helix in the voltage sensor by one helical turn (~5 Å). When this displacement occurs, the S4 helix changes its contact with the pore at two different interfaces. When these changes are observed in fewer than four voltage sensors, the pore remains open, but when they are observed in all four voltage sensors, the pore constricts. The constriction occurs because the S4 helix, as it displaces inward, squeezes the right-handed helical bundle of pore-lining S6 helices. A similar conformational change occurs upon hyperpolarization of the EAG1 channel but with two helical turns displaced instead of one. Therefore, while Kv2.1 and EAG1 are from distinct architectural classes of voltage-dependent ion channels, called domain-swapped and non-domain-swapped, the way the voltage sensors gate their pores is very similar.
    Keywords:  Kv2.1 channel; cryo-EM; membrane potential; potassium channel; voltage gating
    DOI:  https://doi.org/10.1073/pnas.2426744122
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