Energy Expenditure during Cell Spreading Induces AMPK Activation and Regulates the Mechanoresponse of Stem Cells

Abstract

Cells respond to the mechanical properties of the extracellular matrix (ECM) through formation of focal adhesions (FAs), re-organization of the actin cytoskeleton and adjustment of cell contractility. These are energy-demanding processes, but a potential causality between mechanical cues and cellular (energy) metabolism remains largely unexplored. Here, we demonstrate that cytoskeletal reorganization and FA formation during cell spreading on stiff substrates lead to a drop in intracellular ATP levels, thereby activating AMP-activated protein kinase (AMPK). The latter then triggers rapid mitochondrial fragmentation and an increase in ATP levels to reinforce cell tension and regulate nuclear localization of YAP/TAZ and Runx2. Genetic ablation of AMPK Thr-172 phosphorylation lowered cellular ATP content and strongly reduced responses to substrate stiffness. Together, these findings reveal the importance of energy expenditure in regulating the mechanoresponse of cells, and point to AMPK as a key mediator of stem cell fate in response to ECM mechanics.