Jaganathan, A. | bioRxiv Science

bioRxiv2024

Mechano-metabolism of adherent cells in 2D and 3D microenvironments

Cells dynamically regulate their morphology, contractility, and metabolism in response to the mechano-chemical properties of their microenvironment. Here, we show matrix stiffness and ligand density jointly govern the bioenergetics of contractile cells through a nonequilibrium active chemo-mechanical model built around a newly introduced cellular metabolic potential. This concept links ATP hydrolysis to mechanosensitive signaling, quantifies the energetic cost of stress fiber assembly, and determines mechanically stable states. The metabolic potential enables quantitative prediction of cell contractility, morphology, and ATP consumption in different stiffness 2D and 3D environments, and we find quantitative agreement with experimental measurements in MDA-MB-231 breast cancer cells. The model further predicts activation of AMPK accompanies increased energetic demands in stiffer microenvironments which we experimentally validate and correlate with increased mitochondrial membrane potential, glucose uptake, and intracellular ATP levels. Together, these findings establish a predictive quantitative framework unifying mechanosensitive control of cell shape and contractility with the metabolic pathways sustaining cellular function across diverse mechanical environments. TeaserMatrix stiffness reshapes the cellular energy budget, driving metabolic adaptation to mechanical demand.

biophysics↗

bioRxiv2023

Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton

The cell nucleus is continuously exposed to external signals, of both chemical and mechanical nature. To ensure proper cellular response, cells need to regulate not only the transmission of these signals, but also their timing and duration. Such timescale regulation is well described for fluctuating chemical signals, but if and how it applies to mechanical signals reaching the nucleus is still unknown. Here we demonstrate that the formation of fibrillar adhesions locks the nucleus in a mechanically deformed conformation, setting the mechanical response timescale to that of fibrillar adhesion remodelling ([~]1 hour). This process encompasses both mechanical deformation and associated mechanotransduction (such as via YAP), in response to both increased and decreased mechanical stimulation. The underlying mechanism is the anchoring of the vimentin cytoskeleton to fibrillar adhesions and the extracellular matrix through plectin 1f, which maintains nuclear deformation. Our results reveal a mechanism to regulate the timescale of mechanical adaptation, effectively setting a low pass filter to mechanotransduction.

biophysics↗