AMPK is a Mechano-Metabolic Sensor Linking Mitochondrial Dynamics to Myosin II Dependent Cell Migration

Cell migration is crucial for development, immunity and cancer dissemination. We find that mitochondrial dynamics control plasticity of cell migration by sensing adhesion levels. Amoeboid cells migrating in 3-dimensions (3D) harbour high Myosin II levels, require low adhesion/traction and harbour a unique metabolome. Mechanistically, low adhesion requires less energy, leading to fragmented mitochondria, lower engagement in OXPHOS, lower ATP production and higher AMPK activation. Molecularly, AMPK activity leads to MYPT1 inactivation and increased Myosin II dynamics. Reducing adhesion, inhibiting mitochondrial fusion or inducing AMPK activity results in cytoskeletal remodelling and efficient rounded-amoeboid 3D migration and invasion. Moreover, AMPK inhibition suppresses amoeboid invasive features and the metastatic potential in vivo. We measure a mitochondrial AMPK driven switch in regions of human tumours where amoeboid cells are actively disseminating. We unveil how mitochondrial dynamics control plasticity of cell migration and suggest AMPK is a master “mechano-metabolic sensor” at the crossroads between energetics and the actomyosin cytoskeleton.