2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction
Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely u...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
1 August 2025
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| In: |
Nature metabolism
Year: 2025, Jahrgang: 7, Pages: 1593-1613 |
| ISSN: | 2522-5812 |
| DOI: | 10.1038/s42255-025-01332-8 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s42255-025-01332-8 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s42255-025-01332-8 
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| Verfasserangaben: | Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A. Wickström, Christian Frezza, and Aleksandra Trifunovic |
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| 245 | 1 | 0 | |a 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction |c Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A. Wickström, Christian Frezza, and Aleksandra Trifunovic |
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| 520 | |a Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite d-2-hydroxyglutarate (d-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that d-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT. | ||
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| 700 | 1 | |a Trifunovic, Aleksandra |e VerfasserIn |4 aut | |
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