Control of neuronal mitochondrial transport.
Doctoral thesis, UCL (University College London).
Synapses consume large amounts of energy, and energy supply to synaptic sites is critical for their proper function. Most energy in the brain is supplied by mitochondria, organelles efficient at utilising oxygen and substrates such as glucose and pyruvate to produce cellular energy in the form of ATP. Due to the large size of many neurons - which precludes the rapid diffusion of ATP from one side of the cell to the other - mitochondria must be positioned close to activated synaptic sites. There must therefore be transport pathways that allow mitochondria to move throughout the cell. As patterns of neuronal activity are constantly changing, these transport pathways must also be able to be controlled on rapid timescales. The molecular mechanisms that underlie the movement of mitochondria have remained elusive. In this study, a mechanism for coupling mitochondria to the microtubule based transport pathway was characterised. Miro1, a mitochondrial membrane protein, was shown to link mitochondria to kinesin motor proteins in a complex with the adaptor protein Trak2. Varying the levels of Miro1 in neurons altered the ability of mitochondria to move throughout the cell. To provide energy to activated synapses, there must be signals that can control mitochondrial movement. This study describes two mechanisms that allow this control. First, GTP dependent recruitment of the adaptor protein Trak2 is shown to control the number of mitochondria transported into neuronal processes. Second, calcium entry through NMDA receptors upon synaptic activation causes a localised stopping of mitochondria around the active sites. This is shown to be caused by calcium inhibiting the Miro1:kinesin interaction and results in recruitment of mitochondria to activated synapses. This study provides a mechanism where local energy demand can be spatially linked to energy production, by controlling mitochondrial transport through the mitochondrial membrane protein Miro1.
|Title:||Control of neuronal mitochondrial transport|
|Additional information:||Authorisation for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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