Methylglyoxal-derived glycation tunes nuclear viscoelasticity
- 1Universite Catholique de Louvain
Abstract
Reactive carbonyl metabolites such as methylglyoxal (MGO) accumulate in diabetes, aging, and metabolic disease, conditions frequently associated with pathological stiffening of human cells and tissues. While glycation of extracellular matrices and cytoskeletal proteins is known to contribute to these mechanical changes, whether the nucleus itself is a direct mechanical target of carbonyl stress remains unknown. Here, by combining advanced atomic force microscopy-based nanomechanical probing with correlative confocal imaging, we show that MGO-derived glycation directly remodels isolated cell nuclei, increasing stiffness, reducing fluidity, and restricting intranuclear deformation propagation. MGO-derived adducts accumulate prominently at the nuclear envelope, and perturbation of lamin A/C and chromatin state reveals that both structures contribute to glycation-induced stiffening. In cells, chronic MGO exposure induces nucleus-intrinsic stiffening and biases YAP nuclear localization in a substrate-stiffness-dependent manner, linking nuclear glycation to altered mechanosensitive regulation. In vivo, cardiac nuclear stiffening is only observed along with increased immunodetected MGO-adduct burden, while nuclear fluidity remains largely preserved. Together, these findings establish nonenzymatic glycation as a metabolic mechanism that remodels nuclear mechanics and alters cellular mechanosensing, revealing a previously unrecognized physical consequence of carbonyl stress.
Related
- Glycation proteomics identifies creatine kinase as a mediator of the effects of methylglyoxal on mitochondrial permeability transition
- Super-resolution mapping of nuclear stress signaling by probiotic-derived extracellular vesicles in UV-induced skin photodamage
- Methylglyoxal hampers the angiogenic capacity of human retinal endothelial cells modifying cell transcriptome with the contribution of NRSF/REST
- Amelogenin-derived peptide-5 suppresses the receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation via adenosine monophosphate-activated protein kinase activation
- Polarization affects viscoelasticity and podosome distribution of primary human macrophages
BibTeX
@misc{alcarazhurtado2026methylglyoxalderived,
title = {{Methylglyoxal-derived glycation tunes nuclear viscoelasticity}},
author = {M. Alcaraz-Hurtado and A. Duchalet and A. Salinas-Torres and E. Musliu and G. Jordanov and J. Rodriguez-Ramos and R. Silva-Rojas and N. Fourny and O. M. Bautista-Aguilera and M. Adrover and J. Alegre Cebollada and L. Bertrand and A. C. Dumitru},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754974},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754974v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Methylglyoxal-derived glycation tunes nuclear viscoelasticity
AU - M. Alcaraz-Hurtado
AU - A. Duchalet
AU - A. Salinas-Torres
AU - E. Musliu
AU - G. Jordanov
AU - J. Rodriguez-Ramos
AU - R. Silva-Rojas
AU - N. Fourny
AU - O. M. Bautista-Aguilera
AU - M. Adrover
AU - J. Alegre Cebollada
AU - L. Bertrand
AU - A. C. Dumitru
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754974
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754974v1
AB - Reactive carbonyl metabolites such as methylglyoxal (MGO) accumulate in diabetes, aging, and metabolic disease, conditions frequently associated with pathological stiffening of human cells and tissues. While glycation of extracellular matrices and cytoskeletal proteins is known to contribute to these mechanical changes, whether the nucleus itself is a direct mechanical target of carbonyl stress remains unknown. Here, by combining advanced atomic force microscopy-based nanomechanical probing with correlative confocal imaging, we show that MGO-derived glycation directly remodels isolated cell nuclei, increasing stiffness, reducing fluidity, and restricting intranuclear deformation propagation. MGO-derived adducts accumulate prominently at the nuclear envelope, and perturbation of lamin A/C and chromatin state reveals that both structures contribute to glycation-induced stiffening. In cells, chronic MGO exposure induces nucleus-intrinsic stiffening and biases YAP nuclear localization in a substrate-stiffness-dependent manner, linking nuclear glycation to altered mechanosensitive regulation. In vivo, cardiac nuclear stiffening is only observed along with increased immunodetected MGO-adduct burden, while nuclear fluidity remains largely preserved. Together, these findings establish nonenzymatic glycation as a metabolic mechanism that remodels nuclear mechanics and alters cellular mechanosensing, revealing a previously unrecognized physical consequence of carbonyl stress.
ER -