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Review Article |
Mitochondrial movement and positioning in axons: the role of growth factor signaling
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-1392, USA
* Author for correspondence (e-mail: phollenb{at}purdue.edu)
Accepted 23 January 2003
The extreme length of axonal processes requires that aerobic ATP production and Ca2+ homeostasis are non-uniformly organized in the cytoplasm. As a result, the transport and positioning of mitochondria along axons is essential for neuronal homeostasis. Mitochondria undergo rapid but intermittent transport in both the anterograde and retrograde directions in axons. We have shown that in chick embryonic sensory neurons, the transport of mitochondria responds to physiological changes in the cell and, particularly, to growth cone activity. When an axon is actively elongating, mitochondria move preferentially anterograde and then become stationary, accumulating in the region of the active growth cone. When axonal elongation ceases, mitochondria in the distal axon resume movement but undergo net retrograde transport and become uniformly distributed along the axon. This redistribution of mitochondria is achieved in two ways: there is a transition between motile and stationary mitochondria and a large up- and downregulation of their anterograde, but not retrograde, motor activity. Mitochondrial transport does not respond to the experimentally induced elongation of axons in the absence of an active growth cone, implying that signals from the active growth cone regulate transport. To determine the nature of these signals, we have focally stimulated the shafts of sensory axons in culture with nerve growth factor (NGF) covalently conjugated to polystyrene beads. We find that mitochondria accumulate at regions of focal NGF stimulation. This response is specific to mitochondria and does not result from general disruption of the cytoskeleton in the region of stimulation. Disruption of the phosphoinositide 3-kinase (PI 3-kinase) pathway, one of the signaling pathways downstream from NGF–receptor binding, completely eliminates NGF effects on mitochondrial behavior in axons. We propose that mitochondrial transport and/or docking are regulated in part via NGF/TrkA/PI 3-kinase signaling.
Key words: mitochondrial movement, sensory axon, nerve growth factor, NGF, phosphoinositide 3-kinase, neuronal homeostasis, growth cone, signaling
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