title: AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion.
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.
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT 05405 University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405.
authors.forename: Brian
authors.initials: B
authors.lastname: Cunniff
authors.affiliation: University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405 Department of Pharmacology, University of Vermont, Burlington, VT 05405.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McKenzie
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT 05405 University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Heintz
authors.affiliation: University of Vermont Cancer Center, University of Vermont, Burlington, VT 05405 Department of Pharmacology, University of Vermont, Burlington, VT 05405 alan.howe@med.uvm.edu.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Howe
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms; D010766:Phosphorylation; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism* / Q000502:physiology
chemical_list: D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases