AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion

Abstract

Mitochondria infiltrate leading edge lamellipodia, increasing local mitochondrial mass and relative ATP concentration. AMPK regulates infiltration of mitochondria into the leading edge of 2D lamellipodia and 3D invadopodia, coupling local metabolic sensing to subcellular targeting of mitochondria during cell movement.

Abstract

Cell migration is a complex behavior involving many energy-expensive biochemical events that iteratively alter cell shape and location. Mitochondria, the principal producers of cellular ATP, are dynamic organelles that fuse, divide, and relocate to respond to cellular metabolic demands. Using ovarian cancer cells as a model, we show that mitochondria actively infiltrate leading edge lamellipodia, thereby increasing local mitochondrial mass and relative ATP concentration and supporting a localized reversal of the Warburg shift toward aerobic glycolysis. This correlates with increased pseudopodial activity of the AMP-activated protein kinase (AMPK), a critically important cellular energy sensor and metabolic regulator. Furthermore, localized pharmacological activation of AMPK increases leading edge mitochondrial flux, ATP content, and cytoskeletal dynamics, whereas optogenetic inhibition of AMPK halts mitochondrial trafficking during both migration and the invasion of three-dimensional extracellular matrix. These observations indicate that AMPK couples local energy demands to subcellular targeting of mitochondria during cell migration and invasion.