Universität zu Köln

Kaul, Harshita ORCID: 0000-0002-3420-2693, Isermann, Lea ORCID: 0000-0003-3319-3999, Senft, Katharina ORCID: 0000-0003-2294-6481, Popovic, Milica ORCID: 0000-0002-8762-6967, Georgomanolis, Theodoros ORCID: 0000-0002-4066-9257, Baumann, Linda, Sivanesan, Pujyanathan ORCID: 0009-0002-2574-3735, Pouikli, Andromachi ORCID: 0000-0003-1868-6875, Nolte, Hendrik ORCID: 0000-0003-1560-5099, Lucic, Bojana, Hildebrandt, Ximena ORCID: 0000-0001-6930-203X, Seidel, Katrin, Gnad, Thorsten ORCID: 0000-0002-7744-4940, Gaedke, Felix ORCID: 0000-0002-7744-4940, Göbel, Ulrike, Peters, Franziska ORCID: 0000-0002-3250-3740, Cherevatenko, Maksym ORCID: 0009-0003-0938-1233, Park, Joo Hyun, Schauss, Astrid ORCID: 0000-0002-6658-2192, Peltzer, Nieves ORCID: 0000-0002-4134-5852, Brüning, Jens Claus ORCID: 0000-0002-6619-0092, Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442, Pfeifer, Alexander ORCID: 0000-0001-8805-6831, Langer, Thomas ORCID: 0000-0003-1250-1462, Lusic, Marina, Wickström, Sara A. ORCID: 0000-0001-6383-6292, Frezza, Christian ORCID: 0000-0002-3293-7397 and Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517 (2025). 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction. Nature Metabolism, 7 (8). pp. 1593-1613. Nature Publ. Group. ISSN 2522-5812

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Abstract

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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Kaul, Harshita UNSPECIFIED https://orcid.org/0000-0002-3420-2693 UNSPECIFIED Isermann, Lea UNSPECIFIED https://orcid.org/0000-0003-3319-3999 UNSPECIFIED Senft, Katharina UNSPECIFIED https://orcid.org/0000-0003-2294-6481 UNSPECIFIED Popovic, Milica UNSPECIFIED https://orcid.org/0000-0002-8762-6967 UNSPECIFIED Georgomanolis, Theodoros UNSPECIFIED https://orcid.org/0000-0002-4066-9257 UNSPECIFIED Baumann, Linda UNSPECIFIED UNSPECIFIED UNSPECIFIED Sivanesan, Pujyanathan UNSPECIFIED https://orcid.org/0009-0002-2574-3735 UNSPECIFIED Pouikli, Andromachi UNSPECIFIED https://orcid.org/0000-0003-1868-6875 UNSPECIFIED Nolte, Hendrik UNSPECIFIED https://orcid.org/0000-0003-1560-5099 UNSPECIFIED Lucic, Bojana UNSPECIFIED UNSPECIFIED UNSPECIFIED Hildebrandt, Ximena UNSPECIFIED https://orcid.org/0000-0001-6930-203X UNSPECIFIED Seidel, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Gnad, Thorsten UNSPECIFIED https://orcid.org/0000-0002-7744-4940 UNSPECIFIED Gaedke, Felix UNSPECIFIED https://orcid.org/0000-0002-7744-4940 UNSPECIFIED Göbel, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Franziska UNSPECIFIED https://orcid.org/0000-0002-3250-3740 UNSPECIFIED Cherevatenko, Maksym UNSPECIFIED https://orcid.org/0009-0003-0938-1233 UNSPECIFIED Park, Joo Hyun UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid UNSPECIFIED https://orcid.org/0000-0002-6658-2192 UNSPECIFIED Peltzer, Nieves UNSPECIFIED https://orcid.org/0000-0002-4134-5852 UNSPECIFIED Brüning, Jens Claus UNSPECIFIED https://orcid.org/0000-0002-6619-0092 UNSPECIFIED Kornfeld, Jan-Wilhelm UNSPECIFIED https://orcid.org/0000-0002-6802-4442 UNSPECIFIED Pfeifer, Alexander UNSPECIFIED https://orcid.org/0000-0001-8805-6831 UNSPECIFIED Langer, Thomas UNSPECIFIED https://orcid.org/0000-0003-1250-1462 UNSPECIFIED Lusic, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickström, Sara A. UNSPECIFIED https://orcid.org/0000-0001-6383-6292 UNSPECIFIED Frezza, Christian UNSPECIFIED https://orcid.org/0000-0002-3293-7397 UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED https://orcid.org/0000-0002-5472-3517 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-811832
Identification Number:	10.1038/s42255-025-01332-8
Journal or Publication Title:	Nature Metabolism
Volume:	7
Number:	8
Page Range:	pp. 1593-1613
Number of Pages:	21
Date:	1 August 2025
Publisher:	Nature Publ. Group
ISSN:	2522-5812
Language:	English
Faculty:	External institution Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81183