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

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

Brian Cunniff; Andrew J. McKenzie; Nicholas H. Heintz; Alan K. Howe

2016

Scholarcy highlights

  • Cell movement is a complex, highly dynamic process that integrates myriad diverse biochemical events to iteratively reshape and relocate the entire cell
  • Mitochondria rapidly and actively traffic into the leading edge of migrating cells In ongoing studies of cell migration and mitochondrial dynamics, we routinely observed mitochondria rapidly trafficking from the cell body into the leading edge of migrating SKOV-3 human ovarian adenocarcinoma cells
  • This behavior is not limited to a particular cell type, tissue origin, or pathological condition, as B16F10 mouse melanoma cells, human malignant mesothelioma cells, HeLa cells, immortalized nontumorigenic human mesothelial cells, and REF52 rat embryo fibroblasts displayed rapid infiltration of mitochondria into lamellipodia
  • This polarized trafficking in motile cells is in stark contrast to the dynamics seen in stationary cells, in which mitochondria are less active and show no net accumulation or positive flux in those regions
  • They demonstrate that mitochondria rapidly traffic into leading edge structures during cell migration and matrix invasion and that this trafficking is driven by AMPactivated protein kinase, a master regulator of cellular energy
  • We found a significant increase in ATP levels within pseudopodia compared with cell bodies
  • The pseudopod purification technique used here to determine this ratio is not amenable to hightime-resolution analyses. Another possibility is that the overall lower ATP:ADP ratio in bulk, purified pseudopodia masks smaller subregions of higher ratios
  • These observations couple the subcellular dynamics of mitochondria to the localized energy demands of cell migration and support a model in which high utilization of ATP within the leading edge of a migrating cell promotes local activation of AMPactivated protein kinase, which in turn stimulates directional microtubule-based trafficking of mitochondria to replenish ATP, which fuels the leading edge migration machinery

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