bims-smemid 2025-08-03 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2025–08–03
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.
2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.

Nat Commun. 2025 Jul 25. 16(1): 6870

Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.

Xiaole Wang, Pengli Wang, Lihang Zhang, Tianyu Xu, Seungkuk Ahn, Upnishad Sharma, Han Yu, Nico Strohmeyer, Daniel J Müller.

Mammalian cells adjust integrin-mediated adhesion based on the composition and structure of the extracellular matrix (ECM). However, how spatially confined ECM ligands regulate cell adhesion initiation remains unclear. Here, we investigate how cells adapt early adhesion to different ECM protein areas. Through combining microcontact printing with single-cell force spectroscopy we measure cell adhesion initiation and strengthening to defined areas of ECM proteins. HeLa cells and mouse embryonic fibroblasts gradually increase adhesion with collagen I or fibronectin area, while reaching maximum adhesion force to ECM patterns having areas above certain thresholds. On much smaller patterns, both cell types switch to a different state and considerably increase the adhesion force per ECM protein area, which they strengthen much faster. This spatially enhanced adhesion state does not require talin or kindlin, indicating a fundamentally different adhesion mechanism. Mechanotransduction seems to play integrin and cell type-specific roles in the spatially enhanced adhesion state.

DOI: https://doi.org/10.1038/s41467-025-62153-7
Nat Metab. 2025 Aug 01.

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.

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, Aleksandra Trifunovic.

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.

DOI: https://doi.org/10.1038/s42255-025-01332-8