AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

Abstract Cell migration are crucial for development, immunity and cancer dissemination. We find that AMPK controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional (3D) matrices, fast migrating amoeboid cancer cells exert low adhesion/low traction linked to lower energy levels; while their low ATP/AMP ratio leads to AMPK activation. In turn, AMPK plays a dual role controlling both mitochondrial dynamics and cytoskeletal remodelling. High AMPK in low adhering migratory cells, induces mitochondrial fission via MFF phosphorylation, resulting in lower OXPHOS and lower mitochondrial ATP. At the same time, AMPK phosphorylates and inactivates MYPT1, increasing Myosin II dependent amoeboid migration. Reducing adhesion, inducing AMPK activity or inhibiting mitochondrial fusion result in profound cytoskeletal remodelling and efficient rounded-amoeboid 3D migration and invasion. Moreover, AMPK inhibition suppresses in vivo metastatic potential of amoeboid cancer cells. We measure a mitochondrial/AMPK-driven switch in regions of human tumours where amoeboid cells are actively disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a master “mechano-metabolic sensor” at the crossroads between energetics and the actomyosin cytoskeleton.