bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–04–13
twenty papers selected by
Xiong Weng, University of Edinburgh
  1. Diet induced insulin resistance is due to induction of PTEN expression.
  2. FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
  3. Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
  4. The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
  5. Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
  6. Acetylation of METTL3: A negative regulator of m6A deposition on chromatin-associated regulatory RNAs.
  7. Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity.
  8. Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
  9. Asparagine transporter supports macrophage inflammation via histone phosphorylation.
  10. Lipolysis-derived fatty acids are needed for homeostatic control of sterol element-binding protein-1c driven hepatic lipogenesis.
  11. Aging-associated mitochondrial decline accelerates skin aging and obesity.
  12. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.
  13. Gut microbial metabolites protect against obesity.
  14. HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.
  15. Identification of RING E3 pseudoligases in the TRIM protein family.
  16. Role of METTL16 in PPARγ methylation and osteogenic differentiation.
  17. Small molecules restore mutant mitochondrial DNA polymerase activity.
  18. A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
  19. Cross-talks between Metabolic and Translational Controls during Beige Adipocyte Differentiation.
  20. Mitochondria and cell death signalling.
  1. bioRxiv. 2025 Mar 26. pii: 2025.03.25.645201. [Epub ahead of print]
    Diet induced insulin resistance is due to induction of PTEN expression.
    Radha Mukherjee, Priya Pancholi, Malvika Sharma, Hilla Solomon, Merna N Timaul, Claire Thant, Rory McGriskin, Omar Hayatt, Vladimir Markov, John D'Allara, Simona Bekker, Jacqueline Candelier, Sebastian E Carrasco, Elisa de Stanchina, Kiran Vanaja, Neal Rosen.
      Insulin resistance is a condition associated with obesity, type 2 diabetes(T2D), hyperinsulinemia, hyperglycemia and defined by reduced sensitivity to insulin signaling. Molecular causes and early signaling events underlying insulin resistance are not well understood. Here we show that insulin activation of PI3K/AKT/mTOR signaling in insulin target tissues, causes mTORC1 induction of PTEN translation, a negative regulator of PI3K signaling. We hypothesized that insulin resistance is due to insulin dependent induction of PTEN that prevents further increases in PI3K signaling. In a diet induced animal model of obesity and insulin resistance, we show that PTEN levels are increased in fat, muscle, and liver. Hyperinsulinemia and PTEN induction are followed by hyperglycemia, severe glucose intolerance, and hepatic steatosis. In response to chronic hyperinsulinemia, PTEN remains increased, while AKT activity is induced transiently before settling down to a PTEN-high and AKT-low state in the tissues, predicted by computational modeling of the PTEN-AKT feedback loop. Treatment with PTEN and mTORC1 inhibitors prevent and reverse the effect of PTEN induction, rescue insulin resistance and increase PI3K/AKT signaling. Thus, we show that PTEN induction by increased insulin levels elevates feedback inhibition of the pathway causing insulin resistance, its associated phenotypes, and is a potential therapeutic target.
    DOI:  https://doi.org/10.1101/2025.03.25.645201
  2. Nat Commun. 2025 Apr 10. 16(1): 3422
    FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
    Xinyi Chen, Jingchen Shao, Isabell Brandenburger, Weikun Qian, Lisa Hahnefeld, Rémy Bonnavion, Haaglim Cho, ShengPeng Wang, Juan Hidalgo, Nina Wettschureck, Gerd Geisslinger, Robert Gurke, Zheng Wang, Stefan Offermanns.
      The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-58706-5
  3. Nat Metab. 2025 Apr 10.
    Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
    Meng Yu, Bing Feng, Jonathan C Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P Eappen, Hesong Liu, Longlong Tu, Kristine M Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang.
      17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2-ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.
    DOI:  https://doi.org/10.1038/s42255-025-01268-z
  4. Nat Commun. 2025 Apr 04. 16(1): 3221
    The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
    Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.
      Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.
    DOI:  https://doi.org/10.1038/s41467-025-58294-4
  5. J Clin Invest. 2025 Apr 08. pii: e169152. [Epub ahead of print]
    Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity.
    Alexandra R Yesian, Mayer M Chalom, Nelson H Knudsen, Alec L Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B Hu, Alexander S Banks, Chih-Hao Lee.
      Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
    Keywords:  Adipose tissue; Cell biology; Glucose metabolism; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169152
  6. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00195-9. [Epub ahead of print]85(7): 1251-1252
    Acetylation of METTL3: A negative regulator of m6A deposition on chromatin-associated regulatory RNAs.
    Yutao Zhao, Chuan He.
      In this issue, Huang et al.1 report the acetylation of METTL3 as a negative regulator of m6A deposition of chromatin-associated regulatory RNAs from enhancers and promoters. This acetylation is mediated by p300 and positively regulated by PAK2.
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.002
  7. Metabolism. 2025 Apr 07. pii: S0026-0495(25)00131-3. [Epub ahead of print] 156262
    Mechanical activation of adipose tissue macrophages mediated by Piezo1 protects against diet-induced obesity by regulating sympathetic activity.
    Shaoqiu Leng, Xiaoyu Zhang, Ruxia Zhao, Nan Jiang, Xinyue Liu, Xin Li, Qi Feng, Zi Sheng, Shuwen Wang, Jun Peng, Xiang Hu.
       OBJECTIVE: Obesity-induced mechanical changes in white adipose tissue (WAT), including adipocyte hypertrophy and fibrosis, are hypothesized to alter adipose tissue macrophage (ATM) function through mechanosensitive pathways. This study aimed to determine whether the mechanosensor Piezo1 in ATMs regulates obesity-associated metabolic dysfunction and thermogenesis.
    METHODS: To investigate macrophage Piezo1 in obesity, myeloid-specific Piezo1-deficient mice (Piezo1∆lyz2) and littermate controls (Piezo1flox/+) were fed a high-fat diet (HFD) to induce obesity for 12 weeks. Metabolic assessments (GTT/ITT), tissue analyses (H&E staining, micro-CT), and RNA-seq were performed. Bone marrow transplantation and co-culture experiments (BMDMs with 3T3L1 adipocytes/PC12 neurons) were performed to evaluate macrophage-adipocyte/neuron crosstalk. Sympathetic activity was tested via cold exposure, NE measurement, and 6-OHDA/αMPT denervation. Molecular mechanisms were investigated using ChIP-qPCR.
    RESULTS: Piezo1∆lyz2 mice exhibited aggravated HFD-induced obesity and insulin resistance despite reduced pro-inflammatory responses. Piezo1 deficiency in ATMs suppressed Slit3-ROBO1 signaling, leading to diminished NE secretion and impaired thermogenesis. Pharmacological inhibition of NE release (6-hydroxydopamine) or ROBO1 knockdown (shROBO1) abolished thermogenic disparities between Piezo1∆lyz2 and control mice. Mechanistically, Piezo1 activation triggered SP1 nuclear translocation, directly binding to the Slit3 promoter to drive Slit3 transcription and secretion.
    CONCLUSION: Piezo1 in ATMs mitigates obesity progression by promoting Slit3-ROBO1-dependent NE secretion and thermogenesis, independent of its pro-inflammatory role. This mechanosensitive pathway links WAT mechanical remodeling to metabolic regulation, which may offer a novel approach for managing obesity.
    Keywords:  Macrophage; Norepinephrine; Obesity; Piezo1; Slit3
    DOI:  https://doi.org/10.1016/j.metabol.2025.156262
  8. Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00112-3. [Epub ahead of print]
    Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue.
    Christopher Auger, Mark Li, Masanori Fujimoto, Kenji Ikeda, Jin-Seon Yook, Timothy R O'Leary, María Paula Huertas Caycedo, Cai Xiaohan, Satoshi Oikawa, Anthony R P Verkerke, Kosaku Shinoda, Patrick R Griffin, Kenji Inaba, Roland H Stimson, Shingo Kajimura.
      Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca2+ cycling via SERCA2b in adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that an endoplasmic reticulum (ER) membrane-anchored peptide, C4orf3 (also known as another regulin [ALN]), uncouples SERCA2b Ca2+ transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3 complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca2+ transport without affecting SERCA2 expression, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of C4orf3 resulted in compensatory activation of UCP1-dependent thermogenesis following cold challenge. We demonstrated that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study identifies C4orf3 as the molecular resistor to SERCA2b-mediated Ca2+ import that plays a key role in UCP1-independent thermogenesis and energy balance.
    Keywords:  Ca(2+) cycling; UCP1-independent; energy balance; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.009
  9. Sci Adv. 2025 Apr 11. 11(15): eads3506
    Asparagine transporter supports macrophage inflammation via histone phosphorylation.
    Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren.
      Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1β (IL-1β) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway-mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.ads3506
  10. Commun Biol. 2025 Apr 09. 8(1): 588
    Lipolysis-derived fatty acids are needed for homeostatic control of sterol element-binding protein-1c driven hepatic lipogenesis.
    Paola Peña de la Sancha, Beatrix Irene Wieser, Silvia Schauer, Helga Reicher, Wolfgang Sattler, Rolf Breinbauer, Martina Schweiger, Margarete Lechleitner, Saša Frank, Rudolf Zechner, Dagmar Kratky, Peter John Espenshade, Gerald Hoefler, Paul Willibald Vesely.
      Sterol Regulatory Element-Binding Protein-1c (SREBP-1c) is translated as an inactive precursor (P-SREBP-1c) postprandially. Low levels of unsaturated fatty acids (uFAs) and high insulin promote its proteolytic activation, yielding N-SREBP-1c that drives fatty acid (FA) biosynthesis. During fasting, however, lipogenesis is low, and adipose tissue lipolysis supplies the organism with FAs. Adipose Triglyceride Lipase (ATGL) is the rate-limiting enzyme for adipose tissue lipolysis, and it preferentially releases uFAs. Therefore, we hypothesized that adipose ATGL-derived uFAs suppress P-SREBP-1c activation in the liver. In this study, we show that (I) N-SREBP-1c is transiently higher in livers of fasted and refed adipose specific Atgl knockout mice than in control livers. (II) This effect is reversed by injection of uFAs. (III) uFAs inhibit endoplasmic reticulum to Golgi-apparatus transport of SREBP Cleavage-Activating Protein (SCAP) in hepatocytes, which is essential for SREBP activation. Our findings demonstrate that adipose tissue ATGL derived uFAs attenuate P-SREBP-1c activation in the liver mainly after refeeding. We propose that this ATGL/SREBP-1c axis adds an additional layer of coordination between lipogenesis and lipolysis.
    DOI:  https://doi.org/10.1038/s42003-025-08002-1
  11. J Invest Dermatol. 2025 Apr 08. pii: S0022-202X(25)00395-1. [Epub ahead of print]
    Aging-associated mitochondrial decline accelerates skin aging and obesity.
    Shuji Yamamura, Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Daisuke Torigoe, Takehisa Suzuki, Michio Sato, Kimi Araki, Akira Suzuki, Satoshi Fukushima, Yuichi Oike.
      Skin tissue, which consists of epidermal, dermal, and hypodermal cells, plays an important role in biological defense and physical appearance. External and internal stresses occurring with aging disrupt skin homeostasis, promoting development of phenotypes associated with aging. While many studies of skin aging focus on the dermis, potential epidermal changes have largely remained uncharacterized. Here, we demonstrate that epidermal cells do not exhibit cellular senescence phenotypes with aging but instead show age-related decreases in mitochondrial number. We also found that mice lacking mitochondrial transcription factor A (TFAM) in epidermal cells exhibit delayed hair regrowth and impaired wound healing by middle age resembling changes seen in skin of aged mice. Furthermore, middle-aged epidermis-specific TFAM-deficient mice exhibited obesity, suggesting that impaired fatty acid metabolism in epidermal cells resulting from mitochondrial decline may lead to obesity. These findings overall suggest that mitochondrial decline occurs as a primary event in epidermal aging, and that anti-aging strategies to enhance activity or number of epidermal mitochondria could antagonize both skin-aging phenotypes and age-related metabolic disease.
    Keywords:  aging; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.jid.2025.03.028
  12. Cell Metab. 2025 Apr 03. pii: S1550-4131(25)00114-7. [Epub ahead of print]
    Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation.
    Eric Ravussin, Guillermo Sanchez-Delgado, Corby K Martin, Robbie A Beyl, Frank L Greenway, Libbey S O'Farrell, William C Roell, Hui-Rong Qian, Jing Li, Hiroshi Nishiyama, Axel Haupt, Edward J Pratt, Shweta Urva, Zvonko Milicevic, Tamer Coskun.
      Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.
    Keywords:  GIP; GLP-1; adaptive thermogenesis; energy balance; energy expenditure; energy intake; fat oxidation; obesity; sleeping metabolic rate; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.011
  13. Nat Rev Endocrinol. 2025 Apr 04.
    Gut microbial metabolites protect against obesity.
    Katrin Legg.
      
    DOI:  https://doi.org/10.1038/s41574-025-01115-x
  14. Sci Rep. 2025 Apr 04. 15(1): 11574
    HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.
    Parker S Woods, Rengül Cetin-Atalay, Angelo Y Meliton, Kaitlyn A Sun, Obada R Shamaa, Kun Woo D Shin, Yufeng Tian, Benjamin Haugen, Robert B Hamanaka, Gökhan M Mutlu.
      HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state but can shift toward glycolysis under hypoxic conditions. Here, we generated mice with tamoxifen-inducible myeloid lineage cell specific deletion of Hif1a (Hif1afl/fl:LysM-CreERT2+/-) and from these mice, we isolated TR-AMs and bone marrow-derived macrophages (BMDMs) in which Hif1a is deleted. We show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a-/- BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. We conclude that HIF-1α regulates mitochondrial function in BMDMs but not in TR-AMs. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in different types of macrophages.
    Keywords:  Alveolar macrophage; Bone marrow-derived macrophage; HIF-1α; Inflammation; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1038/s41598-025-95962-3
  15. Nat Commun. 2025 Apr 11. 16(1): 3456
    Identification of RING E3 pseudoligases in the TRIM protein family.
    Jane Dudley-Fraser, Diego Esposito, Katherine A McPhie, Coltrane Morley-Williams, Tania Auchynnikava, Katrin Rittinger.
      TRIpartite Motif (TRIM) family proteins have diverse roles across a broad variety of cellular functions, which are largely presumed to depend on their ubiquitin E3 ligase activity, conferred by a RING domain. However, recent reports have shown that some TRIMs lack detectable ubiquitination activity in isolation, despite containing a RING domain. Here, we present parallel in cellulo, in vitro, and in silico structure-function analyses of the ubiquitin E3 ligase activity and RING domain structural characteristics of the whole TRIM protein family. In-depth follow-up studies of this comprehensive dataset reveals a number of 'pseudoligases', whose RING domains have structurally diverged at either the homodimerisation or E2~ubiquitin interfaces, thereby disrupting their ability to catalyse ubiquitin transfer. Together, these data raise intriguing open questions regarding the unknown TRIM functions in physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-025-58807-1
  16. Cell Death Dis. 2025 Apr 10. 16(1): 271
    Role of METTL16 in PPARγ methylation and osteogenic differentiation.
    Liangjie Lu, Lijun Wang, Minjie Yang, Huihan Wang.
      Osteoporosis, a prevalent bone disease, is characterized by the deterioration of bone tissue microstructure and imbalanced osteogenesis. The regulatory role of PPARγ m6A methylation mediated by METTL16 remains poorly elucidated. This study utilized advanced single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq techniques to explore how METTL16 influences the osteogenic differentiation of Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs) and its implication in osteoporosis. The research revealed that METTL16 enhances the suppression of osteogenic differentiation in BMSCs, while PPARγ is associated with BMSC ferroptosis. Mechanistically, METTL16 facilitates the m6A modification of PPARγ transcription, thereby promoting ferroptosis in BMSCs and impeding their osteogenic differentiation. The in vivo animal experiments confirmed the pivotal role of the METTL16-PPARγ axis in osteoporosis development in mice. These findings suggest that the regulation of PPARγ m6A methylation by METTL16, leading to ferroptosis, is a critical mechanism impacting BMSC osteogenic differentiation and the pathogenesis of osteoporosis.
    DOI:  https://doi.org/10.1038/s41419-025-07527-x
  17. Nature. 2025 Apr 09.
    Small molecules restore mutant mitochondrial DNA polymerase activity.
    Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.
      Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.
    DOI:  https://doi.org/10.1038/s41586-025-08856-9
  18. EMBO Mol Med. 2025 Apr 09.
    A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
    Abi S Ghifari, Martin Ott.
      
    DOI:  https://doi.org/10.1038/s44321-025-00232-4
  19. Nat Commun. 2025 Apr 09. 16(1): 3373
    Cross-talks between Metabolic and Translational Controls during Beige Adipocyte Differentiation.
    Daehwa Youn, Boseon Kim, Dahee Jeong, Ju Yeon Lee, Seha Kim, Dulguun Sumberzul, Rehna Paula Ginting, Min-Woo Lee, Ju Hwan Song, Ye Seul Park, Yumin Kim, Chang-Myung Oh, Mihye Lee, Jun Cho.
      Whether and how regulatory events at the translation stage shape the cellular and metabolic features of thermogenic adipocytes is hardly understood. In this study, we report two hitherto unidentified cross-talk pathways between metabolic and translational regulation in beige adipocytes. By analysing temporal profiles of translation activity and protein level changes during precursor-to-beige differentiation, we found selective translational down-regulation of OXPHOS component-coding mRNAs. The down-regulation restricted to Complexes I, III, IV, and V, is coordinated with enhanced translation of TCA cycle genes, engendering distinct stoichiometry of OXPHOS and TCA cycle components and altering the related metabolic activities in mitochondria of thermogenic adipocytes. Our high-resolution description of ribosome positioning unveiled potentiated ribosome pausing at glutamate codons. The increased stalling is attributable to remodelled glutamate metabolism that decreases glutamates for tRNA charging during pan-adipocyte differentiation. The ribosome pauses decrease protein synthesis and mRNA stability of glutamate codon-rich genes, such as actin cytoskeleton-associated genes.
    DOI:  https://doi.org/10.1038/s41467-025-58665-x
  20. Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510
    Mitochondria and cell death signalling.
    Ella Hall-Younger, Stephen Wg Tait.
      Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102510
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