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The Journal of Neuroscience, August 13, 2008, 28(33):8306-8315; doi:10.1523/JNEUROSCI.2614-08.2008

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Cellular/Molecular
Mitochondrial Membrane Potential in Axons Increases with Local Nerve Growth Factor or Semaphorin Signaling

Jessica Verburg and Peter J. Hollenbeck

Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47906

Correspondence should be addressed to Peter J. Hollenbeck, Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN 47906. Email: phollenb{at}purdue.edu

Neurons concentrate mitochondria at sites in the cell that have a high demand for ATP and/or calcium buffering. To accomplish this, mitochondrial transport and docking are thought to respond to intracellular signaling pathways. However, the cell might also concentrate mitochondrial function by locally modulating mitochondrial activity. We tested this hypothesis by measuring the membrane potential of individual mitochondria throughout the axons of chick sensory neurons using the dye tetramethylrhodamine methylester (TMRM). We found no difference in the TMRM mitochondrial-to-cytoplasmic fluorescence ratio (F_m/F_c) among three functionally distinct regions: axonal branch points, distal axons, and the remaining axon shaft. In addition, we found no difference in F_m/F_c among stationary, retrogradely moving, or anterogradely moving mitochondria. However, F_m/F_c was significantly higher in the lamellipodia of growth cones, and among a small fraction of mitochondria throughout the axon. To identify possible signals controlling membrane potential, we used beads covalently coupled to survival and guidance cues to provide a local stimulus along the axon shaft. NGF- or semaphorin 3A-coupled beads caused a significant increase in F_m/F_c in the immediately adjacent region of axon, and this was diminished in the presence of the PI3 (phosphatidylinositol-3) kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or the MAP (mitogen-activated protein) kinase inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio]butadiene), demonstrating that signaling pathways downstream of both ligands affect the _m of mitochondria. In addition, general inhibition of receptor tyrosine kinase activity produced a profound global decrease in F_m/F_c. Thus, two guidance molecules that exert different effects on growth cone motility both elicit local, receptor-mediated increases in membrane potential.

Key words: mitochondria; membrane potential; growth cone; axonal transport; cell signaling; growth factor

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Received June 9, 2008; accepted July 1, 2008.

Correspondence should be addressed to Peter J. Hollenbeck, Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN 47906. Email: phollenb{at}purdue.edu

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